Stereotactic Radiosurgery Dose Research Articles

SURG-43. PATTERNS OF FAILURE FOLLOWING REIRRADIATION WITH GAMMA KNIFE STEREOTACTIC RADIOSURGERY FOR RECURRENT HIGH-GRADE GLIOMAS

Abstract Re-irradiation with stereotactic radiosurgery (SRS) is an increasingly used treatment for recurrent high-grade glioma (HGG). We analyzed the patterns of failure and outcomes of salvage Gamma Knife SRS for recurrent HGG to better identify which patients would most benefit. We reviewed all patients who received SRS for recurrent HGG from January 2008 to May 2020. Pattern of failure was defined by the distance of recurrence from the SRS isodose line as follows: in-field local, marginal local, regional local, and distant failure. Overall survival (OS), progression-free survival (PFS), and local-failure free survival (LFS) were estimated using Kaplan-Meier methods, and regression model analysis was performed to analyze clinical predictors of failure. A total of 146 patients with HGG underwent SRS treatment to 410 target lesions. The median target volume was 3.3 cm3 and median total dose was 18 Gy. Sixty-one (41.8%) patients developed progression following SRS. PFS at 6 and 12 months were 65.8% and 37.3% respectively. Median OS was 12.4 months from salvage SRS. There were 113 (79.5%) local failures (53.1% in-field, 45.1% marginal, and 1.8% regional), 2 (1.4%) distant, and 27 (19%) concomitant local and distant failures. LFS at 6 and 12 months was 82.9% and 66.6%, respectively. Non-white race (HR = 0.37), SRS dose ≥ 20 Gy (HR = 0.34), age < 60 years (HR = 0.43), and KPS ≥ 70 (HR = 0.44) were associated with longer time to local failure. Non-white race (HR = 5.55) and SRS dose ≥ 20 Gy (HR = 5.62) were associated with more distant failure. No grade 4 or 5 toxicity was observed. In conclusion, the dominant pattern of failure remains local and in-field despite conformal dose distribution with SRS and infiltrative tumor histology. This supports the role of reirradiation with SRS in well selected patients with recurrent HGG.

RBIO-04. OUTCOMES OF RADIOSURGERY FOR WHO GRADE 2 MENINGIOMAS: THE ROLE OF KI-67 INDEX IN GUIDING THE TUMOR MARGIN DOSE

Abstract The management of WHO grade 2 meningiomas is complicated by their diverse clinical behaviors. Stereotactic radiosurgery (SRS) can be an effective management option. Literature on SRS dose selection is limited, but suggests a higher dose is better for tumor control. We aimed to characterize the predictors of post-SRS outcomes that can help guide planning and management. We reviewed a cohort of consecutive patients with pathologically-proven WHO grade 2 meningiomas who underwent SRS at a single institution between 2011 and 2023. Ninety-nine patients (median age 62 years) underwent SRS, eleven of whom received hypofractionated SRS in 5 fractions. Twenty-two patients had received prior irradiation. The median follow-up was 49 months. The median overall survival (OS) was 119 months (95%CI 92–NA) with estimated 5- and 10-year survival of 83% and 27% respectively. The median progression-free survival (PFS) was 40 months (95%CI 32–62) with 3- and 5-year rates at 54% and 35% respectively. The median locomarginal PFS was 63 months (95%CI 51.8-NA) with 3- and 5-year rates at 65% and 52%. Nine (9%) patients experienced adverse events, 2 CTCAE grade 3 and 7 grade 2, consisting of worsening neurologic deficit from edema. In the single-session SRS cohort, Ki-67 was a significant predictor of both OS and intracranial PFS. Tumors with Ki-67 >10% had ~10 times risk of locomarginal progression compared to Ki-67 ≤10% (p<0.001). In tumors with Ki-67 >10%, margin dose ≥14 Gy was associated with significantly better tumor control, but not for tumors with Ki-67 ≤ 10%. Other significant predictors of tumor control were prescription dose, tumor volume, and location. The management of WHO grade 2 meningiomas requires a multi-modality approach. This study demonstrated the value of a targeted SRS approach in patients with limited disease, and further establish predictive biomarkers that can guide planning through a personalized approach.

Outcomes of Radiosurgery for WHO Grade 2 Meningiomas: The Role of Ki-67 Index in Guiding the Tumor Margin Dose.

The management of World Health Organization (WHO) grade 2 meningiomas is complicated by their diverse clinical behaviors. Stereotactic radiosurgery (SRS) can be an effective management option. Literature on SRS dose selection is limited but suggests that a higher dose is better for tumor control. We characterize the predictors of post-SRS outcomes that can help guide planning and management. We reviewed a cohort of consecutive patients with pathologically-proven WHO grade 2 meningiomas who underwent SRS at a single institution between 2011 and 2023. Ninety-nine patients (median age 62 years) underwent SRS, 11 of whom received hypofractionated SRS in 5 fractions. Twenty-two patients had received previous irradiation. The median follow-up was 49 months. The median overall survival was 119 months (95% CI 92-NA) with estimated 5- and 10-year survival of 83% and 27%, respectively. The median progression-free survival (PFS) was 40 months (95% CI 32-62), with 3- and 5-year rates at 54% and 35%, respectively. The median locomarginal PFS was 63 months (95% CI 51.8-NA) with 3- and 5-year rates at 65% and 52%. Nine (9%) patients experienced adverse events, 2 Common Terminology Criteria for Adverse Events grade 3 and 7 grade 2, consisting of worsening neurologic deficit from edema. In the single-session cohort, Ki-67 significantly predicted both overall survival and intracranial PFS. Tumors with Ki-67 >10% had 2.17 times the risk of locomarginal progression compared with Ki-67 ≤10% (P = .018) adjusting for covariates. Sex, prescription dose, tumor volume, and location also predicted tumor control. In tumors with Ki-67 >10%, margin dose ≥14 Gy was associated with significantly better tumor control but not for tumors with Ki-67 ≤10%. The management of WHO grade 2 meningiomas requires a multimodality approach. This study demonstrates the value of a targeted SRS approach in patients with limited disease and further establishes predictive biomarkers that can guide planning through a personalized approach.

Clinicogenomic predictors of survival and intracranial progression after stereotactic radiosurgery for colorectal cancer brain metastases.

Brain metastases (BM) from colorectal cancer (CRC) are associated with dismal prognosis. When BM-directed therapy is considered, better methods are needed to identify patients at risk of poor oncological outcomes in order to optimize patient selection for closer surveillance or escalated therapy. The authors sought to identify clinicogenomic predictors of survival and intracranial disease progression after CRC BM have been treated with stereotactic radiosurgery (SRS). Patients with newly diagnosed CRC BM treated with SRS between 2009 and 2022 who had next-generation genomic sequencing data available were included. Frameless SRS was delivered in 1-5 fractions, alone or after neurosurgical resection. Outcomes included overall survival (OS) and intracranial progression (IP), evaluated per patient treated with SRS, and local progression (LP), evaluated per BM. Associations between baseline clinicogenomic features and outcomes were evaluated with Cox regression and competing risk regression, with death as a competing risk. This analysis included 123 patients with 299 BM. At BM diagnosis, 111 patients (90%) had progressive extracranial disease, and 79 patients (64%) had ≥ 3 sites of extracranial metastasis. The median (IQR) number of BM was 2 (1-3) per patient. The median (IQR) biologically effective dose (BED) was 51.3 (51.3-65.1) Gy, corresponding to a prescription of 27 Gy in 3 fractions. OS, IP, and LP estimates at 1 year after SRS were 36%, 55%, and 12%, respectively. OS was independently associated with progressive extracranial disease (HR 4.26, 95% CI 1.63-11.2, p = 0.003) and ≥ 3 extracranial metastatic sites (HR 1.84, 95% CI 1.12-3.01, p = 0.02). LP was less likely when BM received BED ≥ 51.3 Gy (HR 0.24, 95% CI 0.07-0.78, p = 0.02), independent of BM diameter (HR 1.21/cm, 95% CI 0.8-1.84, p = 0.4). IP was independently associated with genomic alterations; TP53 driver alterations were associated with higher risk of IP (HR 2.71, 95% CI 1.26-5.79, p = 0.01), whereas MYC pathway alterations were associated with lower risk (HR 0.15, 95% CI 0.03-0.68, p = 0.01). The authors identified clinicogenomic features associated with adverse outcomes after SRS for CRC BM. Progressive and extensive extracranial metastases predicted worse OS. Insufficient SRS doses predicted greater risk of LP. Wild-type TP53 and alterations in the MYC pathway were independently associated with lower risk of IP. Patients at high risk of IP may be considered for closer surveillance or escalated therapy.

Frameless LINAC Stereotactic Radiosurgery for Brain Metastasis using VMAT: A Review of 20 Cases and Institutional Experience

Background/Objectives: Brain metastases can be treated with Stereotactic Radiosurgery (SRS), a precise radiation therapy approach. This study aimed to review the feasibility and efficacy of frameless LINAC-based SRS using Volumetric Modulated Arc Therapy (VMAT) in a group of 20 patients. Methods: Twenty patients diagnosed with brain metastases received VMAT SRS. Clinical characteristics such as demographics, gender, performance status, number of brain metastases, neurological symptoms, neurosurgical procedures, systemic status, prior treatments, lesion size, SRS dose, local control after SRS and toxicity profile were assessed. Results: The median age of patients was 49.5 years (range 32-63), with 80% being female. Most patients (85%) had ECOG scores of 0-1. The median lesion size treated was 16 mm, with a median dose of 20 Gy for the first SRS (SRS1). After SRS1, 75% of patients achieved Local Control (LC), with a median duration of LC of 7.65 months. Six patients received a second SRS (SRS2) with a median dose of 20 Gy to a different location. Two out of six patients achieved LC after SRS2. Radiation necrosis occurred in 2 cases (10%). The median follow-up time from brain metastasis to the last follow-up was 20.31 months (range 0-50.43 months). Conclusion: Frameless LINAC-based VMAT SRS appears to be a promising treatment option for brain metastases. Initial findings suggest favorable local control rates and further research is needed to optimize treatment strategies.

Frameless LINAC Stereotactic Radiosurgery for Brain Metastasis using VMAT: A Review of 20 Cases and Institutional Experience

Background/Objectives: Brain metastases can be treated with Stereotactic Radiosurgery (SRS), a precise radiation therapy approach. This study aimed to review the feasibility and efficacy of frameless LINAC-based SRS using Volumetric Modulated Arc Therapy (VMAT) in a group of 20 patients. Methods: Twenty patients diagnosed with brain metastases received VMAT SRS. Clinical characteristics such as demographics, gender, performance status, number of brain metastases, neurological symptoms, neurosurgical procedures, systemic status, prior treatments, lesion size, SRS dose, local control after SRS and toxicity profile were assessed. Results: The median age of patients was 49.5 years (range 32-63), with 80% being female. Most patients (85%) had ECOG scores of 0-1. The median lesion size treated was 16 mm, with a median dose of 20 Gy for the first SRS (SRS1). After SRS1, 75% of patients achieved Local Control (LC), with a median duration of LC of 7.65 months. Six patients received a second SRS (SRS2) with a median dose of 20 Gy to a different location. Two out of six patients achieved LC after SRS2. Radiation necrosis occurred in 2 cases (10%). The median follow-up time from brain metastasis to the last follow-up was 20.31 months (range 0-50.43 months). Conclusion: Frameless LINAC-based VMAT SRS appears to be a promising treatment option for brain metastases. Initial findings suggest favorable local control rates and further research is needed to optimize treatment strategies.

Proposal of an Alternative Near-Minimum Isodose Surface DV-0.01 cc Equally Minimizing Gross Tumor Volume Below the Relevant Dose as the Basis for Dose Prescription and Evaluation of Stereotactic Radiosurgery for Brain Metastases.

Introduction In stereotactic radiosurgery (SRS) for brain metastasis (BM), the prescribed dose is generally reported as a minimum dose to cover a specific percentage (e.g. D98%) of the gross tumor volume (GTV) with or without a margin or an unspecified intended marginal dose to the GTV boundary. In dose prescription to a margin-added planning target volume (PTV), the GTV marginal dose is likely variable and unclear. This study aimed to revealmajor flaws of dose prescription to a fixed % coverage of a target volume (TV), such as GTV D98% or PTV D95%, and to propose an alternative. Materials and methods Seven quasi-spherical models with volumes ranging from 1.00 to 15.00 cc were assumed as GTVs. The GTVs and the volumes generated by adding isotropic 1- and 2-mm margins to the GTV boundaries (GTV + 1 and 2 mm) were used for SRS planning, dose prescription, and evaluation. Volumetric-modulated arcs with a 5-mm leaf-width multileaf collimator were used to optimize each SRS plan to ensure the steepest dose gradient outside each TV boundary. In dose prescription to the GTV D98%, 0.02-0.3 cc of the GTV is below the prescribed dose, and the volume increases with larger GTVs. The volume below the prescribed dose should be less than the equivalent of a 3-mm-diameter lesion, i.e. 0.01 cc. Therefore, DV-0.01 cc was defined as an alternative near-minimum dose for which the TV below a relevant dose is less than 0.01 cc. Four different dose prescriptions, including the GTVDV-0.01 cc, were compared using specific doses in 1, 3, and 5 fractions, equivalent to 80, 60, and 50 Gy, respectively, as biologically effective doses (BEDs) to the boundaries of GTV, GTV + 1 mm, and GTV + 2 mm, respectively. Results Dose prescription to the GTV DV-0.01 cc corresponds to 95.0, 98.0, and 99.0-99.93% coverages for the GTV of 0.20, 0.50, and 1.00-15.00 cc, respectively. The GTV DV-0.01 cc varied substantially and decreased significantly as the GTV increased in dose prescriptions to the GTV D98%, GTV + 1 mm D95%, and GTV + 2 mm D95%. The GTV + 2 mm DV-0.01 cc increased significantly as the GTV increased, except for the dose prescription to the GTV + 2 mm D95% with a decreasing tendency. When comparing BED-based specific dose prescriptions, dose prescription to the GTV DV-0.01 cc was optimal in terms of the following: 1) consistency of the near-minimum dose of GTV; 2) the highest BED at 2 mm outside the GTV, except for 1.00 cc GTV, and the rational increase with increasing GTV; and 3) the highest BED at 2 mm inside the GTV. In dose prescription with the BED of 80 Gy in 1 fraction and 5 fractionsto the GTV DV-0.01 cc, the GTV limits were ≤1.40 and ≤8.46 cc, respectively, in order for the irradiated isodose volume not to exceed the proposed thresholds for minimizing the risk of brain radionecrosis. Conclusions Dose prescription to a fixed % coverage of a GTV with or without a margin leads to the substantially varied near-minimum doseat the GTV boundary, which significantly decreases with increasing GTV.Alternatively, GTV DV-0.01 cc with a variable coverage (D>95%) for >0.20 cc GTV and fixedD95% for ≤0.20 cc GTV is recommended as the basis for dose prescription and evaluation, along with supplemental evaluation of the marginal dose of the GTV plus a margin (e.g. GTV + 2 mm) to demonstrate the appropriateness of dose attenuationoutside the GTV boundary.

Salvage Stereotactic Radiosurgery for Recurrent WHO Grade 2 and 3 Meningiomas: A Multicenter Study (STORM)

PurposeThe role of stereotactic radiosurgery (SRS) in the management of grade 2 and 3 meningiomas is not well elucidated. Unfortunately, local recurrence rates are high, and guidelines for management of recurrent disease are lacking. To address this knowledge gap, we conducted STORM, a multicenter retrospective cohort study of patients treated with primary SRS for recurrent grade 2 and 3 meningiomas. Methods and MaterialsData on patients with recurrent grade 2 and 3 meningioma treated with SRS at first recurrence were retrospectively collected from eight academic centers in the United States. Patients with multiple lesions at the time of initial diagnosis or more than two lesions at the time of first recurrence were excluded from this analysis. Patient demographics and treatment parameters were extracted at time of diagnosis, first recurrence, and second recurrence. Oncologic outcomes including progression-free survival (PFS) and overall survival (OS) as well as toxicity outcomes were reported at the patient level. ResultsFrom 2000-2022, 108 patients were identified (94% grade 2, 6.0% grade 3). 106 patients (98%) had upfront surgical resection (60% gross-total resection) with 18% receiving adjuvant radiotherapy (RT). Median time to first progression was 2.5 years (IQR 1.34-4.30). At first recurrence, patients were treated with single or fractionated SRS to a median marginal dose of 16 Gy to a maximum of two lesions (87% received single fraction SRS). Median follow-up time after SRS was 2.6 years. 1-, 2-, and 3-year PFS was 90%, 75%, and 57%, respectively after treatment with SRS. 1-, 2-, and 3-year OS was 97%, 94%, and 92%, respectively. On multivariable analysis, grade 3 disease (HR 6.80; 95% CI 1.61-28.6), male sex (HR 3.48; 95% CI 1.47-8.26), and receipt of prior RT (HR 2.69; 95% CI 1.23-5.86) were associated with worse PFS. SRS dose and tumor volume were not correlated with progression. Treatment was well-tolerated, with a 3.0% incidence of grade 2+ radiation necrosis. ConclusionsThis is the largest multi-center study to evaluate salvage SRS in recurrent grade 2 and 3 meningiomas. In this select cohort of patients with primarily grade 2 meningioma with potentially more favorable natural history of delayed, localized first recurrence amenable to salvage SRS, local control rates and toxicity profiles were favorable, warranting further prospective validation.

1134 A Call to Revise the Thirty-year-old SRS Dose Guidelines for Brain Metastases

INTRODUCTION: Stereotactic Radiosurgery (SRS) currently is the most widely used neurosurgical strategy for treatment of brain metastases. Many centers still rely on 30-year-old dose volume guidelines derived from RTOG 90-05. METHODS: Between 2014 and 2020 330 NSCLC patients (median age = 65 years) with 2910 brain metastases underwent Gamma knife SRS. The number of tumors treated per patient ranged from 1-56 and the total tumor cumulative volume ranged from .05 to 33.09 cc (median = 3.17). The median prescribed tumor margin dose was 18 Gy. RESULTS: Median overall survival after radiosurgery was 15.5 months. Radiological tumor progression was noted 66 out of 2910 tumors (2.27%) in 51 out of 330 patients (15.45%). Tumors were divided into 4 categories based on tumor volumes (<1.5 cc, 1.5-<5 cc, 5-<10 cc, and = 10cc). The effect of margin dose, and % tumor covered in 18 Gy, 20 Gy, and 24 Gy on local tumor control was analyzed for all 4 categories. In tumors with volumes >1.5 cc local tumor control was significantly better (P < 0.05) when =65% of the tumor volume received at least 24 Gy. No relationship was found between tumor control and 75, 90, and 100 % volumes receiving 18 or 20 Gy. CONCLUSIONS: In this study neither conformality of dose delivery nor tumor margin doses were the most important predictors of local tumor control as long as =65% of the tumor volume received at least 24 Gy. This finding can serve as a prescriptive guideline that allows margin doses below the RTOG guidelines, reduces reliance on strict conformality, and improves tumor control.

Predicting stereotactic radiosurgery outcomes with multi-observer qualitative appearance labelling versus MRI radiomics

Qualitative observer-based and quantitative radiomics-based analyses of T1w contrast-enhanced magnetic resonance imaging (T1w-CE MRI) have both been shown to predict the outcomes of brain metastasis (BM) stereotactic radiosurgery (SRS). Comparison of these methods and interpretation of radiomics-based machine learning (ML) models remains limited. To address this need, we collected a dataset of n = 123 BMs from 99 patients including 12 clinical features, 107 pre-treatment T1w-CE MRI radiomic features, and BM post-SRS progression scores. A previously published outcome model using SRS dose prescription and five-way BM qualitative appearance scoring was evaluated. We found high qualitative scoring interobserver variability across five observers that negatively impacted the model’s risk stratification. Radiomics-based ML models trained to replicate the qualitative scoring did so with high accuracy (bootstrap-corrected AUC = 0.84–0.94), but risk stratification using these replicated qualitative scores remained poor. Radiomics-based ML models trained to directly predict post-SRS progression offered enhanced risk stratification (Kaplan–Meier rank-sum p = 0.0003) compared to using qualitative appearance. The qualitative appearance scoring enabled interpretation of the progression radiomics-based ML model, with necrotic BMs and a subset of heterogeneous BMs predicted as being at high-risk of post-SRS progression, in agreement with current radiobiological understanding. Our study’s results show that while radiomics-based SRS outcome models out-perform qualitative appearance analysis, qualitative appearance still provides critical insight into ML model operation.

CTNI-09. DOSE ESCALATION FOR NEOADJUVANT STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: PHASE I RESULTS

Abstract BACKGROUND Surgical resection may be required for large and symptomatic brain metastases. Adjuvant radiotherapy or stereotactic radiosurgery (SRS) is needed to reduce local recurrence. Adjuvant radiosurgery has been associated with higher rates of leptomeningeal failure and radionecrosis. We conducted a phase I trial for brain metastases greater than 2 cm in size to determine the safety of preoperative SRS at escalating doses. METHODS Radiosurgery dose was escalated at 3 Gy increments starting with RTOG 90-05 dosing for 3 cohorts based on maximum tumor diameter: 18 Gy for >2-3 cm, 15 Gy for >3-4 cm, and 12 Gy >4-6 cm. Dose limiting toxicity (DLT) was defined as grade III or greater acute toxicity. Patients underwent surgical resection within 2 weeks and were followed with imaging and physical evaluations every 3 months. RESULTS For tumor size >2-3 cm, patients were enrolled up to the second dose level (21 Gy); for >3-4 cm and >4-6 cm cohorts the third dose level (21 Gy and 18 Gy, respectively) was reached. 35 patients were enrolled with 36 brain metastases treated with preoperative radiosurgery. There were 2 DLT (wound issues) in the >3-4 cm arm at the third dose level and 1 DLT (hemorrhage) in the >4-6 cm arm at the third dose level. The maximal tolerated SRS dose (MTD) for >-2-3 cm arm was not reached, for >3-4 cm arm was 18 Gy and for >4-6 cm arm was 18 Gy. With a median follow-up of 64 months, the 6- and 12-month local control rates were 88.8% and 79.1%, respectively. The 2-year rate of LMD was 0%. CONCLUSION This Phase I preoperative SRS dose escalation trial found a MTD for brain metastases greater than 3 and up to 6 cm in size. The phase II trial will be conducted at the maximum tolerated SRS doses.

NIMG-02. ADVERSE RADIATION EFFECT VERSUS TUMOR PROGRESSION FOLLOWING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: IMPLICATIONS OF RADIOGRAPHIC UNCERTAINTY

Abstract Despite efforts from RANO to standardize treatment response reporting, adverse radiation effect (ARE) following stereotactic radiosurgery (SRS) for brain metastases (BM) remains challenging to distinguish from tumor progression (TP) due to radiographic uncertainty (RU), often necessitating serial imaging until definitive diagnosis (DD) is resolved. We characterized management and implications of RU after BM irradiation for multiple primary tumor histologies. We identified 138 BM cases reviewed at our multi-disciplinary SRS Tumor Board (TB) for RU of ARE versus TP on MRI following SRS between 2015-2022. Target diameter (mm), histology, location, and SRS dose (Gy) on initial treatment and lesion diameter, associated symptoms, and supportive medications at the time of TB presentation were extracted from the medical record. Final lesion etiology, use of any intervention, and neurologic deficits upon DD were documented. Time from RU to DD was calculated. Median time from SRS to initial RU was 11.3 months (IQR 5.5-18.2). Median RU lesion diameter was 14.0 (IQR 8.0-20.0). At the time of RU, 43% of patients were symptomatic, 28% and 4% requiring steroids and bevacizumab, respectively. Time to DD following RU was > 6 and 12 months in 28% and 8% of patients, respectively (maximum 47 months). Median lesion diameter at DD was 16.0 mm (IQR 10.3-24.0). Most (54%) had a DD of ARE, while 41% had TP; 23% and 77% were diagnosed pathologically and radiographically, respectively. Upon DD, 41% underwent local intervention with surgery and/or re-irradiation and 25% had a new neurologic deficit, including weakness (7%), ataxia (5%), and aphasia (4%). In an interdisciplinary setting, it took > 6 months to reach a DD after RU in > 25% of patients previously irradiated for BM. Diagnostic uncertainty and delay may lead to sub-optimal outcomes and symptom burden. Improved characterization of post-SRS imaging findings is needed in this population.

RADT-12. GENOMIC CHARACTERISTICS AND CLINICAL OUTCOMES OF STEREOTACTIC RADIOSURGERY FOR COLORECTAL CANCER BRAIN METASTASES

Abstract PURPOSE Brain metastases (BM) from colorectal cancer (CRC) portend a limited prognosis but are poorly understood, both clinically and biologically. This study defined the clinical outcomes and genomic features of CRC BM treated with stereotactic radiosurgery (SRS). METHODS Patients with newly diagnosed CRC BM treated with SRS at a single institution between 2009 and 2022 were included. Next-generation targeted sequencing using MSK-IMPACT of at least one intracranial or extracranial tumor was required. Overall survival (OS) was evaluated using Kaplan-Meier analysis. Intracranial progression (IP) and local recurrence (LR) were evaluated using competing risk analysis, accounting for death. RESULTS We identified 124 patients with 304 BM, of which, 66 BM received SRS postoperatively. The median prescription was 27 Gy in 3 fractions. Median OS after SRS was 7 months. Poorer KPS, progressive extracranial disease, and lung metastases independently predicted poorer OS. Twelve months after SRS, cumulative incidences of IP and LR were 37% per patient and 6.1% per lesion treated, respectively. Three or more BM at diagnosis independently predicted earlier IP. Biologically effective dose less than the median predicted LR, independent of tumor size. Genomic data were obtained from 68 primary tumors, 63 extracranial metastases, and 33 BM. BM demonstrated significantly greater fraction genome altered, chromosomal instability, and TP53 alterations compared to extracranial metastases and primary tumors. Among patients who had IP, compared to those who had no IP within 6 months, BM contained more frequent alterations in KRAS (56% vs. 43%), SMAD4 (44% vs. 0%), and APC (77% vs. 57%). CONCLUSIONS Among CRC BM treated with SRS, OS and IP were correlated with extracranial and intracranial disease burden, and LR was correlated with SRS dose. Genomic characteristics differed between BM and extracranial disease, and between patients who did and did not experience IP. Further investigation of these genomic differences is underway.

RADT-20. STEREOTACTIC RADIOSURGERY FOR 15 OR MORE BRAIN METASTASES

Abstract BACKGROUND 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. METHODS 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. RESULTS A total of 124 patients treated with LINAC-based SRS were included. 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). 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% and alopecia in 2.4%. Median follow-up was 5.1 months(m). When cognitive data were available, 25 of 31 patients had a stable or improved PROMIS score. The 12m local control was 97.6% while overall intracranial control was 20.8%. One-year freedom from neurological death, leptomeningeal disease, and salvage WBRT were 85.6%, 87.6% and 71.7% respectively. Median overall survival(OS) from brain metastases diagnosis was 11.3m(95% CI 7.2m – 15.3m). On univariate analysis, no prior WBRT(p = 0.038), higher KPS(p = 0.002) and systemic therapy after SRS(p < 0.001) predicted for improved OS. CONCLUSIONS 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. Our study supports further randomized studies comparing SRS and memory avoidance WBRT approaches for patients with ≥ 15 BMs.

Hyperarc Vmat and Vmat planning for stereotactic radiosurgery in multiple brain metastases

Automated treatment planning systems are available for linear accelerator (LINAC) based single and more isocenter multitarget stereotactic radiosurgery (SRS) of brain metastases. HyperArc Volumetric Modulated Arc Therapy (HA-VMAT) is a relatively new isocentric Volumetric Modulated Arc Therapy (VMAT) technique developed specifically for non-coplanar, multileaf collimator (MLC)-based stereotactic radiotherapy with automatic treatment optimization and dose delivery. The HA-VMAT planning approach was developed to accommodate dosing procedures for brain metastases stereotactic radiosurgery. In this study, it was aimed to compare the dosimetric parameters of treatment plans created with single and multi-isocenter retrospectively VMAT and HA-VMAT techniques in patients with lung cancer and multiple brain metastases (4–7) who received single and multi-fraction stereotactic radiosurgery (SRS). Using VMAT and HA-VMAT techniques, two separate treatment plans were created for each case, and tumor target coverage (homogeneity index (HI); conformity index (CI); gradient index (GI)) and organ at risk (OAR) were evaluated dosimetrically. Physical properties and Monitor unit (MU) values of both treatment approaches were compared. Treatment plans were created for study purposes and patients were not treated with these plans. In the study, HI (p = 0.000), CI (p = 0.000) and GI (p = 0.002) values calculated with the HA-VMAT technique are superior to the VMAT technique. Medium-low dose spreads (V4Gy-V16Gy) were significantly reduced in HA-VMAT plans compared to plans with VMAT. HA-VMAT plans result in lower MU than VMAT plans. HA-VMAT planning has significantly less radiation necrosis indicator (V8Gy-V16Gy) compared to VMAT plans. However, there are few studies investigating the ability of the HA-VMAT technique to create high-quality treatment plans for extracranial lesions. HA-VMAT may constitute one of the new options for SRS dose delivery for both single target and multiple targets.

Effect of Cobalt-60 Treatment Dose Rate on Arteriovenous Malformation Obliteration After Stereotactic Radiosurgery With Gamma Knife.

Stereotactic radiosurgery (SRS) marginal dose is associated with successful obliteration of cerebral arteriovenous malformations (AVM). SRS dose rate-how old the cobalt-60 sources are-is known to influence outcomes for some neurological conditions and benign tumors. The objective of this study was to determine the association between cobalt-60 treatment dose rate and cerebral AVM obliteration in patients treated with SRS. We performed a retrospective cohort study of 361 patients undergoing 411 AVM-directed SRS treatments between 2005 and 2019 at a single institution. Lesion characteristics, SRS details, obliteration dates, and post-treatment toxicities were recorded. Univariate and multivariate regression analyses of AVM outcomes regarding SRS dose rate (range 1.3-3.7 Gy, mean = 2.4 Gy, median = 2.5 Gy) were performed. At 10 years post-SRS, 68% of AVMs were obliterated on follow-up imaging. Dose rates >2.9 Gy/min were found to be significantly associated with AVM obliteration compared with those <2.1 Gy/min ( P = .034). AVM size, biologically effective dose, and SRS marginal dose were also associated with obliteration, with obliteration more likely for smaller lesions, higher biologically effective dose, and higher marginal dose. Higher dose rates were not associated with the development of post-SRS radiological or symptomatic edema, although larger AVM volume was associated with both types of edema. Patients with cerebral AVMs treated with higher SRS dose rates (from newer cobalt-60 sources) experience higher incidences of obliteration without a significant change in the risk of post-treatment edema.

Immune checkpoint inhibition and single fraction stereotactic radiosurgery in brain metastases from non-small cell lung cancer: an international multicenter study of 395 patients.

Approximately 80% of brain metastases originate from non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are frequently utilized in this setting. However, concerns remain regarding the risk of radiation necrosis (RN) when SRS and ICI are administered concurrently. A retrospective study was conducted through the International Radiosurgery Research Foundation. Logistic regression models and competing risks analyses were utilized to identify predictors of any grade RN and symptomatic RN (SRN). The study included 395 patients with 2,540 brain metastases treated with single fraction SRS and ICI across 11 institutions in four countries with a median follow-up of 14.2months. The median age was 67years. The median margin SRS dose was 19Gy; 36.5% of patients had a V12 Gy ≥ 10 cm3. On multivariable analysis, V12 Gy ≥ 10 cm3 was a significant predictor of developing any grade RN (OR: 2.18) and SRN (OR: 3.95). At 1-year, the cumulative incidence of any grade and SRN for all patients was 4.8% and 3.8%, respectively. For concurrent and non-concurrent groups, the cumulative incidence of any grade RN was 3.8% versus 5.3%, respectively (p = 0.35); and for SRN was 3.8% vs. 3.6%, respectively (p = 0.95). The risk of any grade RN and symptomatic RN following single fraction SRS and ICI for NSCLC brain metastases increases as V12 Gy exceeds 10 cm3. Concurrent ICI and SRS do not appear to increase this risk. Radiosurgical planning techniques should aim to minimize V12 Gy.

Effect of Cobalt-60 Calibration Dose-Rate on Arteriovenous Malformation Obliteration after Stereotactic Radiosurgery

Stereotactic radiosurgery (SRS) dose rate - how old the cobalt-60 sources are - is known to influence outcomes for some neurologic conditions and benign tumors, but it is not known if SRS dose rate influences arteriovenous malformation (AVM) obliteration. The objective of this study is to determine the association between cobalt-60 calibration dose rate and cerebral AVM obliteration in patients treated with SRS. Our hypothesis is that higher SRS dose rates are associated with increased incidence of cerebral AVM obliteration. We performed a retrospective study of 361 patients undergoing 411 AVM-directed SRS treatments between 2005 and 2019 at a single institution. Obliteration was confirmed with digital subtraction angiogram or MRI (if patient refused angiography). Lesion characteristics, SRS treatment details, and post-treatment obliteration and toxicities were recorded. Univariate and multivariate proportional hazards regression models of AVM outcomes with regard to SRS dose rate were performed, controlling for factors such as Spetzler-Martin Grade, maximum AVM extent, prior hemorrhage and prior embolization. At 10 years post-SRS, 68% of AVMs were obliterated on follow-up imaging. Dose rates >2.9 Gy/min were found to be significantly associated with AVM obliteration compared to those <2.1 Gy/min (p = 0.034, Gray's test). AVM size or Spetzler-Martin grade were also associated with obliteration, with obliteration more likely for smaller lesions, particularly those <3 cm in maximal diameter, or with lower Spetzler-Martin grade. Higher dose rates were not associated with development of post-SRS radiologic or symptomatic edema, though larger AVM volume was associated with both types of edema. Patients with cerebral AVMs treated with higher SRS dose rates (from fresh cobalt-60 sources) experience higher incidences of obliteration, without a significant change in the risk of post-treatment edema. These findings suggest that clinics offering SRS for AVMs should regularly renew cobalt-60 radiation sources to maintain high therapeutic dose rates.

Multi-Institutional Study of Stereotactic Radiosurgery for Recurrent WHO Grade 2/3 Meningiomas: An Interim Analysis

Meningiomas are the most common tumors of the central nervous system (CNS). Approximately 80% are classified as World Health Organization (WHO) grade 1, while 20% correspond to grade 2 or grade 3. In those with grade 2/3 disease, local recurrence is not uncommon. Salvage treatment options vary widely and include resection, external beam radiation therapy (EBRT), stereotactic radiosurgery (SRS), and/or clinical trials. Although retrospective studies have reported on the use of upfront SRS in grade 2/3 meningiomas, large-scale outcomes with SRS in the recurrent setting are lacking. The objective of this study was to report on oncologic outcomes for patients with recurrent grade 2/3 meningioma treated with SRS. This is an ongoing multi-institutional retrospective cohort study. Eligibility criteria include patients >18 years old with pathologically confirmed WHO grade 2 or 3 meningioma treated with SRS monotherapy at the time of first recurrence. Patients require pathologic confirmation only at time of diagnosis; those with upfront grade 1 disease must have pathologic confirmation of grade 2/3 disease at time of first recurrence. Patients with multifocal disease upfront were excluded from this study. A total of 60 patients met eligibility criteria. Baseline demographics at time of initial diagnosis are shown in table 1. At the time of first recurrence, 57 (95%) were WHO grade 2, and 3 (5%) were grade 3. Median follow up time from first recurrence was 5.02 years. Median marginal SRS dose was 16 Gy (IQR 14-17) to a 2.67cc planning treatment volume (IQR 1.4-5.1). 92% of patients received single fraction SRS. Median time to second recurrence was 5.92 years. 1, 3, and 5-year progression-free survival (PFS) was 95%, 68%, and 51%, respectively. 1, 3, and 5-year overall survival (OS) was 100%, 98%, and 96%, respectively. On multivariate analysis, grade 3 disease was independently associated with worse PFS (HR 15.7, p = 0.03). Median SRS dose and treatment volume did not correlate with PFS. 1 patient (1.7%) experienced symptomatic radiation necrosis requiring steroids, 3 (5.0%) experienced new seizure activity, and 2 (3.3%) additional patients showed clinical evidence of post-treatment neurocognitive decline. Based on this interim analysis, primary SRS for recurrent grade 2/3 meningioma appears safe and feasible, with outcomes comparable to prospective data on high-risk grade 2/3 patients treated with post-operative fractionated EBRT. We look forward to further analysis with a larger cohort which may help guide further prospective studies.

Outcomes of a Single Isocenter Brain Multi-Metastases Linear Accelerator Delivered Stereotactic Radiosurgery (SRS)

The management of brain metastases has evolved from using 2D whole brain radiotherapy (WBRT) to more complex techniques like stereotactic radiosurgery (SRS) for patients with limited disease. Long-term control of lesions is challenging with WBRT techniques but treating multiple lesions with traditional SRS, where each lesion is treated on its own isocenter, can be time-consuming and difficult on patients, especially those with claustrophobia. Single Isocenter Multiple Metastases (SIMM) SRS has emerged as an option to deliver ablative SRS doses simultaneously to multiple brain metastases using a single isocenter, thereby limiting the duration of treatments for patients. Though appealing, SIMM SRS adds technical complexity and could potentially lead to worse outcomes or more complications relative to traditional SRS treatments. Given the current paucity of clinical evidence supporting SIMM SRS, we sought to retrospectively review our institution's outcomes and complications for patients treated with SIMM SRS to determine the efficacy and safety of this approach in our hands. Patients treated at our institution with SIMM SRS with at least one post-treatment brain MRI were identified. Date on patient clinical characteristics, planning, and treatment characteristics, and outcomes were retrospectively collected. Post-treatment tumor control was evaluated with follow-up MRI imaging based on RANO criteria. Correlation between tumor control and toxicity was done by assessing radiation doses, PTV coverage, and normal brain V12 constraints. A total of 27 patients received SIMM SRS from January 2015 to February 2022. The median age at first SIMM SRS was 61 (range: 38-87). The most common disease sites were lung (63.0%), breast (18.5%), and GI (7.4%). The 27 patients had 47 SIMM SRS treatments of 163 lesions total. The median number of lesions treated per isocenter was 3 (range: 2-9). 5 patients had 2 SIMM SRS isocenters treated on the same day, treating clusters of lesions (ranging from 5-11 lesions treated on that day). The most common locations involved were frontal, cerebellar, and parietal lobes (32.52%, 21.47%, and 15.34%). The modal dose was 22 Gy (range: 18-24 Gy). Median OS from initial primary diagnosis was 23.23 months, and 9.92 months after the first SIMM SRS treatment. The median imaging follow-up was 9.8 months per lesion, and the local control rate was 95.03%. 2 lesions (1.23%) developed radiation necrosis and the median time to RT necrosis among those lesions was 5.7 months after treatment. The utilization of SIMM SRS demonstrates acceptable efficacy and safety as it has been implemented at our institution. Further studies to evaluate this planning modality are warranted to establish suitable candidates for SIMM SRS as well as evaluate the long-term outcomes for these patients.