Single-fraction Radiosurgery Research Articles

Radiotherapy for subependymal giant cell astrocytoma: time to challenge a historical ban? A case report and review of the literature

BackgroundSubependymal giant cell astrocytoma is a benign brain tumor that occurs in patients with tuberous sclerosis complex. Surgical removal is the traditional treatment, and expert opinion is strongly against the use of radiotherapy. Recently, success has been reported with the mTor inhibitor everolimus in reducing tumor volume, but regrowth has been observed after dose reduction or cessation.Case reportWe present the case of a 40-year-old Asian female patient treated successfully for growing bilateral subependymal giant cell astrocytoma with fractionated stereotactic radiotherapy before everolimus became available. After a follow-up of 8 years, everolimus was administered for renal angiomyolipoma and the patient was followed up until 13 years after radiotherapy. Successive magnetic resonance imaging demonstrated an 80% volume reduction after radiotherapy that increased to 90% with everolimus. A review of the literature was done leveraging Medline via PubMed, and we assembled a database of 1298 article references and 780 full-text articles in search of evidence for contraindicating radiotherapy in subependymal giant cell astrocytoma. Varying results of single-fraction radiosurgery were described in a total of 13 cases. Only in two published cases was the radiation dose of fractionated radiotherapy mentioned. One single publication mentions an induced secondary brain tumor 8 years after whole-brain radiotherapy.ConclusionThere is no evidence of contraindication and exclusion of fractionated radiotherapy in treating subependymal giant cell astrocytoma. Our experience demonstrates that subependymal giant cell astrocytoma, as other benign intracranial tumors, responds slowly but progressively to radiotherapy and suggests that fractionated stereotactic radiotherapy holds promise to consolidate responses obtained with mTor inhibitors avoiding regrowth after cessation.

Radiation Necrosis following SRS or FSRT with Higher BED for Brain Metastases >20 mm

In the RTOG 90-05 study, the maximum tolerated dose of single-fraction radiosurgery (SRS) for lesions 21-30 mm was 18 Gy (BED 45 Gy12). However, patients of the RTOG study were previously irradiated with median 60 Gy (brain tumors) or 30 Gy (brain metastasis). Thus, the max. tolerated BED for lesions not irradiated before may be >45 Gy12. This study investigated safety and efficacy of SRS or fractionated stereotactic radiotherapy (FSRT) with BED >49 Gy12 for radiotherapy-naive brain metastases >20 mm. Data of 169 patients who received SRS or FSRT alone with BED >49 Gy12 for 1-4 brain metastases (2011-2022) were retrospectively analyzed. Thirty-two patients had lesions >20 mm (21-30 mm, n = 27; 21-40 mm, n = 4; >40 mm, n = 1). SRS was performed with 20 Gy (n = 9; 53.3 Gy12) or 19 Gy (n = 2; 49.1 Gy12), prescribed to the 60-80% isodose line (PTV = GTV). FSRT was Linac-based delivering 3 x 10 Gy (n = 3; 55 Gy12), 3 x 11 Gy (n = 4; 63.3 Gy12), 7 x 6 Gy (n = 1; 63 Gy12), 9 x 5 Gy (n = 1; 63.8 Gy12), 10 x 4 Gy (n = 11; 53.3 Gy12), or 12 x 4 Gy (n = 1; 64 Gy12), prescribed to the 80% isodose line (PTV = GTV+1-2 mm). SRS and FSRT were compared for grade ≥2 radiation necrosis (RN), local control (LC) and survival (OS). Fractionation [SRS (n = 89) vs FSRT (n = 48)] and lesion size (≤20 vs >20 mm) were studied in terms of RN rates. Kaplan-Meier method and log-rank test were used for univariate analyses and the Cox proportional hazards model for multivariate analyses. In patients with lesions >20 mm, SRS and FSRT were compared (Fisher's exact/Chi square test) for age, gender, KPS, year of SRS/FSRT, primary tumor, number/site of lesions, systemic treatment, and extracranial metastases. In patients with lesions >20 mm, significantly more patients receiving SRS had a KPS >80 than patients treated with FSRT (91% vs 29%, p = 0.002); otherwise, distributions of patient characteristics were balanced. In patients with lesions >20 mm, SRS was associated with significantly higher RN rates at 1 year (50% vs 9%) and 2 years (50% vs 9%) on univariate analysis (p = 0.012), which remained on multivariate analysis (HR: 0.10; 95% CI: 0.01-0.94, p = 0.044). No significant differences were found for LC (p = 0.21) at 1 year (75% vs 70%) and 2 years (75% vs 53%), and OS (p = 0.09) at 1 year (36% vs 59%) and 2 years (27% vs 46%). In patients with lesions ≤20 mm, 1- and 2-year RN rates following SRS were both 4%, compared to 0% and 15% respectively after FSRT (p = 0.60). In the SRS group, RN rates were significantly higher with lesions >20 mm (vs ≤20 mm) on univariate (p<0.001) and multivariate (HR: 3.82, 95% CI: 1.70-8.58, p = 0.001) analyses. In the FSRT group, max. diameter had no significant impact on RN rates (p = 0.93). Given the limitations of this study, FSRT with BED >49 Gy12 appears associated with a low risk of RN when used for brain metastases >20 mm. SRS with 1x19-20 Gy may not be optimal for metastases >20 mm but appears safe for lesions ≤20 mm. Prospective trials are warranted.

Post-Operative Stereotactic Radiotherapy for Resected Brain Metastases: Results of the Multicenter Analysis (AURORA) of the German Working Group "Stereotactic Radiotherapy"

While the results of prospective studies support the use of postoperative stereotactic radiotherapy (RT) to the resection cavity (RC) as the standard of care after surgery, there are several issues that need to be investigated such as factors for improving local control, risk of leptomeningeal disease and radiation necrosis. Further, the optimal dose and fractionation is still under debate. The working group "Stereotactic Radiotherapy" of the German Society of Radiation Oncology (DEGRO) analyzed its multi-institutional database with 661 patients who received postoperative stereotactic RT to the RC. Treatment was performed at 13 centers between 2008 and 2021. Patient characteristics, treatment details, and follow-up data including overall survival (OS), local control (LC) were evaluated. Cox Regression and Kaplan-Meier curves with Log-rank Tests were calculated for selected variables. In this retrospective study, overall survival was 61.5% at 1 year, 47.6% at 2 years, and 35.5% at 3 years, and local control was 84.6% at 1 year, 74.8% at 2 years, and 72.8% at 3 years. 96% of patients were treated with hypofractionated stereotactic radiotherapy (HSRT), only 26 patients received single fraction radiosurgery (4%). Prognostic factors associated with overall survival were Karnofsky Performance Status, RPA and GPA class, controlled primary tumor and absence of extracranial metastases, whereas prognostic factor associated with local control was planning target volume (23 mL or less). HSRT is the most common fractionation form in the treatment of RCs in this multicenter analysis. This approach results in excellent OS and LC outcomes. OS in patients with resected brain metastases is mainly influenced by performance status. In regard to local control, RT of large cavities remain a challenge with significantly worse outcome.

Assessment of Local and Regional Control in Atypical (WHO Grade 2) Meningiomas Receiving Fractioned Stereotactic Radiotherapy

The optimal delivery of postoperative radiotherapy to WHO grade 2 or atypical meningiomas (AM) is controversial. The historical standard of care has been high dose fractionated radiation to the resection bed and a 2 cm CTV as in RTOG 0539. Single fraction radiosurgery offers a more conformal alternative with demonstrated local control for smaller AM in less sensitive areas. Though less studied, fractionated stereotactic radiosurgery (FSRT) promises safer treatment of larger AM in more sensitive locations while minimizing the treated volume. This single institution retrospective review examines the hypothesis that local and marginal failure patterns in AM treated with five fraction FSRT remain unacceptably high. Thirty-nine patients received 27.5 - 30 Gy in 5 fractions to their AM from 2009 to 2022 with grading based on the WHO criteria active at the time of treatment. All treatments were frameless VMAT deliveries with no PTV margin. Histological diagnosis of AM, gross disease at time of FSRT, five fraction FSRT, and lack of prior local radiation were required for inclusion. Single fraction treatments were excluded. Local recurrence was defined similar to RECIST criteria as an increase of 20% in the greatest cross-sectional diameter on MRI (or CT if MRI contraindicated) with at least one voxel touching the prescription volume. To examine the role of CTV margin, marginal recurrence was defined as any new lesion outside of the prescription volume but within 2 cm of the resection cavity. High grade toxicity per CTCAE v5 was an irreversible grade 3 or any grade 4 toxicity. Resection for radionecrosis was considered a local failure if any viable tumor was seen on pathology. Median follow up was 32.5 months (range 3.2-147.5 months). The number of AM treated post STR, post GTR recurrence, and definitively were 26, 16, and 5 respectively. 3-year local tumor control was estimated to be 84%. As expected, larger tumors were more likely to fail locally (p >.001). Two (5%) patients experienced high grade toxicity - both symptomatic radionecrosis requiring resection. Three-year marginal control was estimated to be 92.3%. Of the 5 tumors treated to the entire resection cavity, none experienced a marginal failure. Interestingly, recurrent tumors s/p GTR were more likely to recur marginally than tumors treated after STR (p = .009). Only 1 (4%) tumor treated after STR failed marginally while 4 (33%) tumors treated after GTR recurrence failed. The rate of high-grade toxicity in AM receiving FSRT was low. Local control appeared comparable to historical rates which may suggest the need for dose escalation with longer term follow-up. Recurrent tumors appear more prone to marginal failures, however more work is needed to determine which patients may benefit from additional CTV margin and more prolonged fractionated dose schedules. Improved targeting with newer imaging studies (e.g., DOTATATE PET) should be examined to determine if more accurate targeting will improve outcomes.

Modeling Gamma Knife Radiosurgical Toxicity for Multiple Brain Metastases

Dosing for single fraction radiosurgery has traditionally relied on tumor measurements from a single maximum diameter. Most protocols recommend setting dosing criteria based on assumed risk of radionecrosis roughly correlating with tumor size. However, the risk of radionecrosis after radiosurgery is best modeled by a function of dose and volume treated, with the largest body of evidence supporting the use of brain tissue receiving ≥12 Gy in one fraction (V12, i.e., > 10.9 cm3). Here we show that tumor surface area (SA) and second order dimensions are superior predictors for Gamma Knife radiosurgical toxicity and can be used to estimate V12. A total of 1217 brain metastases from 245 patients treated with a prescribed dose from 13 to 27 Gy in one fraction were retrospectively reviewed. Eight independent modeling parameters were considered; 3 geometric tumor characteristics: SA, volume (V), and largest axial dimension (LAD) and 5 treatment planning variables: prescription dose (Rx), coverage, selectivity, gradient index, and number of shots. Linear regression and power-law formulations were performed to determine which parameters were the most accurate predictors of V12. The power model is dependent on a conceptualized "pseudo surface area" (PSA), defined as the surface area of a sphere with a diameter of LAD of a lesion (PSA = π*LAD2). At the aggregate patient level, the model predicts total brain V12 by summing the V12 values for each singular lesion only by using LAD and Rx as input variables. Tumor SA was the best univariate linear predictor of V12 (adjR2 = 0.770), followed by LAD (adjR2 = 0.755) and V (adjR2 = 0.745). The SA predictive model improves for lesions that have high sphericity > 0.85 (adjR2 = 0.837), with a measure of 1 indicating a perfect sphere. Using bivariable regression analysis, we formulated a single term power model that even more accurately predicts for V12 (V12 = 0.0137 * Rx1.5 * LAD2, adjR2 = 0.906) and is proportional to PSA. At the patient level, this model also accurately predicts for total brain V12 (adjR2 = 0.896) and V12 > 10.9 cm3 (Sensitivity = 99.1%, Specificity = 90.5%). Conceptually, SA univariately predicts for V12 more accurately than other tumor physical dimensions or treatment planning parameters, while the best bivariable power model involves PSA. We provide a preplan model for brain metastases that can help better estimate radionecrosis risk, determine prescription doses given a target V12, and provide safe dose escalation strategies without the use of any planning software.

Single-Fraction Pre-Operative Stereotactic Radiosurgery for Early-Stage Breast Cancer: Pathological Findings

to assess pathological results after single-fraction pre-operative stereotactic radiosurgery of early-stage breast cancer. A phase 2 clinical trial to investigate the feasibility of pre-operative radiosurgery for early-stage breast cancer was conducted. Eligible patients are women older than 50 years, with histologically proven breast invasive ductal carcinoma, hormonal receptors positive/human epidermal grow factor receptor 2 negative, any grade, tumor size < 3cm, unifocal, with no nodal involvement, and suitable for breast conservative surgery. An expert radiologist injected ultrasound-guided a fiducial marker to precisely identify tumor positioning. The Planning Target Volume (PTV) is created by adding a 3mm margin to the Gross Tumor Volume (GTV). A single fraction of 30-33 Gy is delivered to 95% of PTV. Patients had a breast MRI scan 6-12 weeks after treatment to evaluate the rate of radiological response. Surgery was performed at 9 to 16 weeks after irradiation. From January 2022 to December 2022, 33 patients underwent single-fraction radiosurgery, of whom 29 had breast conserving surgery (BCS). BCS was performed at 9-10 weeks for the first 14 patients, at 14-16 weeks for 13 patients, and at 18-19 weeks for 2 patients. The pathological response was defined as complete response (pCR) if no residual tumor cells were found, partial response (pPR), or no response. The pPR were also subdivided into 3 subgroups according to the rate of residual disease: < 10%, 10-50%, and > 50%. Two patients (7%) achieved pCR, both treated with 33 Gy and operated at 14 weeks. Twenty-five patients (86%) had pPR, of which 7 patients (24%) had residual disease < 10%, 9 patients (31%) between 10-50% and 9 patients (31%) over 50%. Two patients (7%) had no pathological response. All patients had sentinel lymph node biopsy at the time of surgery. Positive micrometastatic nodal involvement was found in 3 patients (11%), of which 2 patients (7%) had macrometastases (pN1a) and received subsequent axillary lymph node dissection. All patients had negative surgical margins. Not any acute and sub-acute surgical complications were observed. Single-fraction pre-operative stereotactic radiosurgery for early-stage breast cancer leads to a high rate of complete or partial pathological response with surgery performed at 2-4 months following irradiation.

Modeling gamma knife radiosurgical toxicity for multiple brain metastases

Background and PurposeRadiation oncology protocols for single fraction radiosurgery recommend setting dosing criteria based on assumed risk of radionecrosis, which can be predicted by the 12 Gy normal brain volume (V12). In this study, we show that tumor surface area (SA) and a simple power-law model using only preplan variables can estimate and minimize radiosurgical toxicity. Materials and MethodsA 245-patient cohort with 1217 brain metastases treated with single or distributed Gamma Knife sessions was reviewed retrospectively. Univariate and multivariable linear regression models and power-law models determined which modeling parameters best predicted V12. The V12 power-law model, represented by a product of normalized Rx dose Rxn, and tumor longest axial dimension LAD (V12 ∼ Rxn1.5*LAD2), was independently validated using a secondary 63-patient cohort with 302 brain metastases. ResultsSurface area was the best univariate linear predictor of V12 (adjR2 = 0.770), followed by longest axial dimension (adjR2 = 0.755) and volume (adjR2 = 0.745). The power-law model accounted for 90% variance in V12 for 1217 metastatic lesions (adjR2 = 0.906) and 245 patients (adjR2 = 0.896). The average difference ΔV12 between predicted and measured V12s was (0.28 ± 0.55) cm3 per lesion and (1.0 ± 1.2) cm3 per patient. The power-law predictive capability was validated using a secondary 63-patient dataset (adjR2 = 0.867) with 302 brain metastases (adjR2 = 0.825). ConclusionSurface area was the most accurate univariate predictor of V12 for metastatic lesions. We developed a preplan model for brain metastases that can help better estimate radionecrosis risk, determine prescription doses given a target V12, and provide safe dose escalation strategies without the use of any planning software.

Radiation Necrosis Following Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy with High Biologically Effective Doses for Large Brain Metastases.

In Radiation Therapy Oncology Group 90-05, the maximum tolerated dose of single-fraction radiosurgery (SRS) for brain metastases of 21-30 mm was 18 Gy (biologically effective dose (BED) 45 Gy12). Since the patients in this study received prior brain irradiation, tolerable BED may be >45 Gy12 for de novo lesions. We investigated SRS and fractionated stereotactic radiotherapy (FSRT) with a higher BED for radiotherapy-naive lesions. Patients receiving SRS (19-20 Gy) and patients treated with FSRT (30-48 Gy in 3-12 fractions) with BED > 49 Gy12 for up to 4 brain metastases were compared for grade ≥ 2 radiation necrosis (RN). In the entire cohort (169 patients with 218 lesions), 1-year and 2-year RN rates were 8% after SRS vs. 2% and 13% after FSRT (p = 0.73) in per-patient analyses, and 7% after SRS vs. 7% and 10% after FSRT (p = 0.59) in per-lesion analyses. For lesions ≤ 20 mm (137 patients with 185 lesions), the RN rates were 4% (SRS) vs. 0% and 15%, respectively, (FSRT) (p = 0.60) in per-patient analyses, and 3% (SRS) vs. 0% and 11%, respectively, (FSRT) (p = 0.80) in per-lesion analyses. For lesions > 20 mm (32 patients with 33 lesions), the RN rates were 50% (SRS) vs. 9% (FSRT) (p = 0.012) in both per-patient and per-lesion analyses. In the SRS group, a lesion size > 20 mm was significantly associated with RN; in the FSRT group, lesion size had no impact on RN. Given the limitations of this study, FSRT with BED > 49 Gy12 was associated with low RN risk and may be safer than SRS for brain metastases > 20 mm.

RADT-03. GOLDILOCKS AND THE THREE DOSES OF RADIOSURGERY FOR SMALL BRAIN METASTASES

Abstract INTRODUCTION The optimal dose for single-fraction radiosurgery (SRS) for small brain metastases (BM) (&amp;lt; 2 cm) has not been established considerable variability in dose selection. METHODS Consecutive patients diagnosed with intact BM &amp;lt; 2 cm in maximum dimension treated with SRS to prescription doses of 24, 22, or 20 Gy on the Gamma Knife® between 3/2019-1/2021 were reviewed. Institutional dosing prescriptions were: 24 Gy for &amp;lt; 10 lesions, 22 Gy for 10-20, and 20 Gy for &amp;gt;20). Endpoints included freedom-from-local-failure (FFLF) and radionecrosis on a per-lesion basis calculated from date of SRS to event. Univariable and multivariable analyses were performed using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS 133 patients with 863 BM met inclusion criteria. Prescription dose was 24 Gy for 416 (48.2%) lesions, 22 Gy for 266 (30.8%), and 20 Gy for 181 (21.0%). 20 Gy was associated (all p&amp;lt; 0.001) with younger age, presence of extracranial-disease, progressive extracranial-disease, lung primary, higher number of BM per SRS course (median 17 for 20 Gy, 14 for 22 Gy, 6 for 24 Gy), and smaller per-lesion tumor volume. With a median follow-up of 15 months, 76 (8.8%) LFs occurred. Actuarial 1-year FFLF was 91.2% (95%CI: 88.6-94.8%) for 24 Gy, 92.5% (89.1-95.9%) for 22 Gy, and 77.9% (71.2-84.6%) for 20 Gy (p&amp;lt; 0.001). On multivariable analysis, factors independently associated with adverse FFLF (all p&amp;lt; 0.05) were male sex, presence of extracranial-disease, breast or lung primary, and 20 Gy prescription dose (HR: 2.52, 95%CI: 1.34-4.76). The cumulative 1-year radionecrosis rate was 7.0% for 24 Gy, 4.0% for 22 Gy, and 3.8% for 20 Gy (p=0.035). CONCLUSION For BM &amp;lt; 2 cm, we propose a testable hypothesis that 22 Gy prescription dose may represent the “Goldilocks zone”- superior to 20 Gy regarding LF and superior to 24 Gy concerning radionecrosis.

RADT-13. CLINICAL OUTCOMES COMPARING RADIOSURGERY TECHNIQUES FOR MANAGING LARGE BRAIN METASTASES

Abstract INTRODUCTION Large brain metastases (BM) are associated with poor local control with single-fraction radiosurgery (SRS) alone. We sought to compare outcomes with various alternative management strategies to assess disease control rates. METHODS Consecutive patients diagnosed with BM ≥ 2 cm in maximum diameter between 3/2019-2/2021 and treated at a single tertiary institution were included. Primary endpoints included freedom-from-local-failure (FFLF) calculated on a per-lesion basis from the date of initial intervention to local failure, and overall survival (OS). Kaplan-Meier analysis and the log-rank test were used. RESULTS 86 patients with 102 large BM met inclusion criteria. The median age was 66 years (range: 31-98), median KPS was 90 (50-100), and 57.8% were female. The most common primary tumor was lung in 40 (39.2%) lesions. The median tumor volume was 9.7 cm3 (2.1-35.5 cm3) and the median maximum tumor diameter was 3.3 cm (2.9-5.6 cm). 37 (36.3%) lesions were treated with staged-SRS, 31 (30.4%) with resection and postoperative-SRS, 21 (20.6%) with preoperative-SRS and resection, and 13 (12.7%) with fractionated-SRS (FSRS). Lesions treated with preoperative-SRS or postoperative-SRS were associated with higher rates of no- or stable-extracranial disease, and larger tumor volumes (preoperative-SRS: median 14.5 cm3 [4.2-33.1]; postoperative-SRS: 18.0 cm3 [2.5-35.5]; FSRS: 5.9 cm3 [2.1-24.6]; staged-SRS: 6.5 cm3 [2.2-27.8]).With a median follow-up of 15.6 months, 12 (11.8%) local failures and 42 (41.2%) deaths occurred. 1-year FFLF and OS for entire cohort were 85.6% (95% CI: 77.9-93.3%) and 64.4% (95% CI: 54.7-74.1%), respectively. The 1-year FFLF (p=0.542)/OS (p=0.043) rates were 94.1%/100% for preoperative-SRS, 84.0%/43.4% for staged-SRS, 81.8%/74.1% for FSRS, and 81.5%/63.4% for postoperative-SRS, respectively. CONCLUSION Although limited by patient numbers, selection bias, and high attrition rate, preoperative-SRS had the numerically most favorable outcomes, supporting this approach for large BM. Prospective evaluation is warranted to determine the optimal management strategy.

Fractionated Radiosurgery Associated with High Rates of Local Control for Large Volume Intact Brain Metastases

<h3>Purpose/Objective(s)</h3> Radiosurgery is a well-established treatment modality for patients with intact brain metastases, and there is a known impact of tumor size and volume on tumor control. Based on desires to improve local control rates and reduce radiation necrosis rates, along with improvements in available technology, fractionated radiosurgery (FSR) is increasingly employed using both linear accelerators (LINAC) and GammaKnife (GK) units. Utilizing our single-institution database, we investigated outcomes for patients with intact brain metastases treated with FSR using LINAC or GK modalities. <h3>Materials/Methods</h3> Institutional records of patients with intact brain metastases treated with FSR were retrospectively reviewed. Patients treated with either GK or LINAC-based FSR were included. Descriptive analyses were performed of primary histology, lesion location, dose/fractionation, modality, tumor volume, and maximum tumor dimension. T-test and chi-square statistics were performed to compare characteristics and outcomes between patients treated with GK versus LINAC FSRT. Kaplan-Meier was used for survival estimates. Univariate analyses and Cox regression models were generated. <h3>Results</h3> 56 patients with 137 brain metastases were reviewed. 67.2% of lesions were treated via GK and 32.8% were treated via LINAC. Median prescription dose was 25 Gy (16-30 Gy) delivered in 2-5 fractions, with a medial lesion volume of 1.27 cc (0.01-77.0 cc). The most common treatment regimens were 24 Gy in 3 fractions and 30 Gy in 5 fractions. The most common primary tumors were lung (38.7%) and breast (28.5%). Median and mean maximum tumor dimension for the entire cohort were 1.73 cm and 2.16 cm (0.27-8.59 cm), respectively. Mean tumor volume was 6.10 cc (0.01-76.97 cc). There was a significant correlation between tumor volume and prescription dose, with larger tumors being more likely to receive a greater number of treatment fractions. The 1-y OS for all patients was 54.1% with a median OS of 15 mos. With a median follow-up of 6 months, the 1-year local control rate was 94.5%. For lesions ≤2 cc, 1-y LC was 97.4% compared to 91% for lesions > 2 cc, though this difference was not statistically significant. On Cox regression, neither maximum tumor dimension nor volume were predictive of local control. Univariate analysis demonstrated increased local recurrence in patients with prior history of neurosurgical intervention. No differences in LC or OS were observed between GK and LINAC. <h3>Conclusion</h3> FSR using 3 to 5 fractions for large volume intact metastases was associated with a high rate of LC compared to rates historically achieved with single fraction radiosurgery for tumors of similar volume. No statistically significant differences in LC or OS were detected according to maximum tumor dimension, volume, fractionation schedule, or treatment modality. FSR should be considered for larger brain metastases to improve LC.

Effectiveness of Standard Margin Stereotactic Radiosurgery Dose to Brain Metastases

This study aims to assess efficacy of a 15-Gy margin dose in terms with the hypothesis that efficacy will be comparable with historical controls with fewer radiation-related side effects. Patients who received single-fraction stereotactic radiosurgery (SRS) for metastatic brain tumors (prescribed 1500 cGy with 2-mm planning tumor volume) at the University of Missouri Hospital between 2004 and 2018 with at least 3 months of follow-up were retrospectively reviewed. Demographics, lesion dimensions, concurrent therapy, and treatment history before SRS were assessed. Outcomes included local control, distant control, radiation-related changes, survival, repeat SRS or whole-brain radiation therapy, and side effects. Data from the literature were pooled for a meta-analysis. A total of 142 patients had at least 3 months of follow-up data available. The 12-month actual local control rate among these patients was 92% per tumor. The overall intracranial control rate was 66.9% per patient. Radiation-related side effects occurred in 32.4% of patients (n= 46), with some patients having more than 1 side effect. Radiation-related radiographic changes occurred in 48 lesions (10.6%) in 37 patients (26%). Pathologically confirmed radiation necrosis occurred in 19 lesions (4%) and in 18 patients (12.6%). Local and distant control rates for this population was comparable with historical controls. Side effects in the literature are inconsistently reported, so rigorous comparative analysis is not possible. A single-fraction radiosurgery margin dose of 15 Gy to the planning tumor volume can effectively provide local control and distant control and is comparable with historical controls, which use 18-25 Gy, with a good toxicity profile.

Hypofractionated Radiosurgery for Large or in Critical-Site Intracranial Meningioma: Results of a Phase 2 Prospective Study

Radiosurgery is a well-known, safe, and effective technique used in the treatment of intracranial meningiomas. However, single-fraction radiosurgery can lead to high toxicity rates when large-volume or critically located lesions are targeted. Multisession-also called hypofractionated-radiosurgery (hypo-RS) might overcome these limitations. Accordingly, we carried out a prospective phase 2 trial, aiming to establish whether a fractionated RS schedule of 25 Gy in 5 fractions would be safe and effective in treating large (≥ 3 cm) and/or critically located (<3 mm from critical structures) grade 1 intracranial meningiomas. The main aim was to evaluate the safety of hypo-RS in terms of absence of adverse events. The secondary aim was to evaluate tumor response in terms of local control, defined as stability or reduction of lesion volume. We prospectively enrolled patients with diagnoses of grade 1 meningiomas, large size and/or critically located lesions, either histologically diagnosed or imaging defined. Additional inclusion criteria were signed informed consent, an age of ≥18 years, and Karnofsky Performance Status ≥70. Between 2011 and 2016, 178 patients were consecutively enrolled. The median follow-up was 53 months (range, 4-101 months). Overall, the toxicity rate was 12.7% (21 of 166 patients). At a 5-year minimum follow-up, the patients' toxicity rates were 11.7 % (9 of 77 patients). Symptom evaluation at both 3-year and last follow-up showed an improvement in most of the patients. Five-year local tumor control was 97% (95% confidence interval, 92%-99%). Hypo-RS schedule of 25 Gy in 5 fractions is a well-tolerated option in the treatment of large-volume and/or critically located benign meningiomas. Early results suggest favorable local control, although longer-term follow-up is needed.

The modern management of untreated large (>2 cm) brain metastases: a narrative review.

Our objective was to identify contemporary management options for large brain metastases reported in literature, specifically evaluating local control and risk of toxicity. Large brain metastases are typically defined as lesions >2 cm in diameter, and historically conferred poor outcomes due to the high rates of radiation necrosis and less local control in comparison to smaller brain metastases. A literature search examining modern management of large brain metastases was performed using ovid-MEDLINE. A total of 18 articles met criteria for review, evaluating single fraction radiosurgery [stereotactic radiosurgery (SRS)] and multi-fraction stereotactic radiation therapy (MFSRT) in both the definitive and post-operative cavity setting, as well as targeted therapies. Multi-fractionated radiosurgery represents a modern and attractive treatment approach in the definitive management of patients with large brain metastases, with equivalent local control and reduced rates of radionecrosis less than 13% in comparison to single fraction SRS. In cases where surgery is indicated, fractionated cavity radiation should be considered for large tumor bed volumes. More research is needed for the optimal dose and fractionation regimen for optimal tumor control with reduced risk of radiation toxicity, but common regimens include 3-5 fractions while meeting appropriate biologically effective dose (BED) goals. Future areas of interest include targeted therapies in the initial management of brain metastases as well as pre-operative radiation therapy to reduce risk of leptomeningeal disease (LMD).

Photon-based High-dose Single-fraction Radiosurgery, an Effective Treatment Modality for Large and Posterior Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignant tumor. This malignancy is frequently treated using brachytherapy, stereotactic radiotherapy, or proton therapy. The objective of this study was to assess the role of stereotactic radiosurgery in the treatment of large and posterior UM. From January 2014 to July 2021, we treated 65 patients (median age=71 years; range=31-89 years) affected by UM. Inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2, life expectancy >6 months, tumor thickness >10 mm, diameter >16 mm or posterior UM. The treatment was delivered with a True Beam™ LINAC with arc modulation technique. All patients received 27 Gy in one fraction (biological effective dose ≈100 Gy, assuming an α/β of 10). The median follow-up was 36 (range=3-90) months. Acute toxicities were reported in 14 patients, whereas late toxicity occurred in 45 (69.2%). Fifteen patients (23.0%) underwent enucleation: eight (12.3%) for failure of local control and seven (10.7%) for late treatment co-morbidities. The 5-year local control, and progression-free, metastasis-free, enucleation-free, and overall survival rates were 80%, 43%, 62%, 65% and 56%, respectively. In multivariate analysis, tumor dimensions significantly influenced survival [larger basal diameter: progression-free [hazard ratio (HR)=2.42] and overall (HR=2.61) survival; greater thickness: overall survival (HR=2.36)]. In multivariate analysis, patients without local control had a higher risk of distant metastasis (HR=3.25). Stereotactic radiosurgery offers an effective and safe approach for selected cases of UM due to the satisfactory results in terms of local control, eye conservation and survival.

Salvage Radiosurgery for Recurrent Cardiac Sarcoma: A Case Report

<h3>Purpose/Objective(s)</h3> Primary cardiac sarcoma is a rare malignant tumor that arises from the cardiac myocardium. Surgical resection is the standard of care and median survival after a R0 resection is typically 6 to 12 months. However, after local recurrence, patients are frequently inoperable with a poor prognosis. The role of salvage chemotherapy and radiation is not well defined. A few case reports have described local control for up to eight months after hypo-fractionated radiosurgery. <h3>Materials/Methods</h3> A 53 year old female presented in October 2017 with acute congestive heart failure and underwent complete surgical resection of undifferentiated pleomorphic sarcoma of the left atrium followed by 6 cycles of adjuvant doxorubicin/hydroxydaunorubicin and ifosfamide. An MRI scan demonstrated an asymptomatic, 24 mm, recurrent atrial mass. The patient elected to proceed with salvage frameless robotic radiosurgery system stereotactic body radiosurgery. We fused CT, MRI, and PET imaging modalities in order to determine the target volume. The tumor was treated with a dose of 7200 cGy in 15 fractions to the 84% isodose line utilizing spine tracking with 4D CT to determine the ITV. Fractionation was used in order to achieve acceptable maximal doses to the main stem bronchus and esophagus. Repeat cardiac MRI at four weeks showed in-field local progression with greater protrusion into the left atrium. The tumor volume doubled in size with invasion of the left ventricle. The patient elected to proceed with salvage frameless robotic radiosurgery system treatment. 2500 cGy in 1 fraction was prescribed to the 76% isodose line in June of 2019. <h3>Results</h3> She tolerated treatment well without any acute toxicity. The patient was subsequently treated with a variety of chemotherapy regimens including TKIs and immunotherapy. Unfortunately, the patient relapsed in December with metastases in the spine and the pelvis. She underwent palliative radiation therapy to multiple bony sites with a partial response. She resumed chemotherapy treatment with TKIs but passed away in June 2020 due to septic shock without evidence of local failure. <h3>Conclusion</h3> Fractionated SBRT was ineffective at controlling our patient's cardiac sarcoma. Our patient demonstrated local control of disease at twelve months after salvage 25 Gy in one fraction radiosurgery without any evidence of cardiac toxicity. High dose single fraction radiosurgery is a reasonable palliative option for long term local control of unresectable cardiac sarcomas.

RADT-30. MULTISESSION RADIOSURGERY ALONE FOR TREATMENT OF PRESUMED MENINGIOMAS: AN INTERIM REPORT FROM A SINGLE INSTITUTION PROTOCOL

Abstract PURPOSE Meningiomas are the most commonly diagnosed primary intracranial tumor. Resection and single-fraction radiosurgery are treatment options with well-established long-term outcomes data. Multisession radiosurgery is an alternative treatment option with promising early results. However, mature outcomes literature does not yet exist. In this study, we report our institution’s interim results on the efficacy and safety of 5-fraction radiosurgery alone for radiographically diagnosed meningiomas. MATERIALS AND METHODS Between 2005-2015 all patients who completed treatment on a single institution protocol utilizing 5-fraction robotic radiosurgery alone for the treatment of progressing radiographically diagnosed meningiomas were eligible for inclusion. Local control was calculated using the Kaplan-Meier Method. RESULTS Forty-four consecutive predominately female patients (84%) ranging in age from 33-85 (median: 59) were included in the present study. Median tumor volume was 4.05mm3 (range: 0.94-15.4mm3) and the majority of tumors were located at the base of skull (66%). A median dose of 25Gy (range: 25Gy-35Gy), was delivered to a median isodose line of 82%, (range: 70%-90%) over a median of 7 days (range: 5-11 days). Acute toxicity was minimal with 7 patients (15%) requiring a short course of steroids for symptomatic edema during treatment. Of 16 patients who presented with a cranial nerve deficit, symptom improvement was noted in 11 patients (69%). No permanent treatment related toxicity was noted in our cohort. The median radiographic follow-up was 6.9 years (range: 0.5-14.8 years). The 5 and 8-year local control rates were 100% and 95%. The median time to local failure (n=2) in our cohort was 8.2 years. CONCLUSIONS The treatment of radiographically diagnosed meningiomas with 5-fraction robotic radiosurgery provides excellent local control to date, with low rates of acute and late toxicity. However, with late failures noted in our series, continued follow-up is needed to determine the optimal dose required for long-term tumor control.

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of radiation therapy in the management of progressive and recurrent glioblastoma in adults.

These recommendations apply to adult patients (18years of age and above) with progressive/recurrent glioblastoma multiforme (pGBM) after first line combined multimodality treatment. Can re-irradiation (by using conventional radiotherapy, fractionated radiosurgery, or single fraction radiosurgery) be used in patients with pGBM after the first adjuvant combined multimodality treatment with radiation and chemotherapy? Level III: When the target tumor is amenable for additional radiation, re-irradiation is recommended as it provides improved local tumor control, as measured by best imaging response. Such re-irradiation can take the form of conventional fractionation radiotherapy, fractionated radiosurgery, or single fraction radiosurgery. Re-Irradiation is recommended in order to maintain or improve a patient's neurological status and quality of life prior to any further tumor progression.

Phase I Dose Escalation Trial of Hypofractionated Radiosurgery for Large Intact or Resected Brain Metastases

<h3>Purpose/Objective(s)</h3> Hypofractionated radiosurgery is often used for large brain metastases (BM) not amenable to single fraction radiosurgery, though the ideal dose-fractionation schedule has not been defined. This phase 1 dose escalation study was designed to define the maximum tolerated dose (MTD) of 5 fraction radiosurgery for intact BM or resection cavities ≥ 3cm and < 6cm in maximal dimension. <h3>Materials/Methods</h3> Dose was escalated according to Escalation with Overdose Control (EWOC) method with a planned total enrollment of 24 patients in 8 patient cohorts of 3 patients per cohort and the target highest acceptable dose limiting toxicity (DLT) rate was set at 25%. Enrollment was closed for 4 months in between each cohort. DLT was defined as any acute or late central nervous system CTCAE toxicity grade ≥ 3 considered possibly related to treatment. DLTs assessment extended through 2 years after treatment or was censored at the time of removal from the study or re-irradiation to the treatment site. <h3>Results</h3> Twenty-four patients with 25 target lesions (5 intact BM, 20 resection cavities) were enrolled from October 2012 – February 2021 at the following dose levels with escalation and de-escalation according to EWOC rules: 6 Gy x 5 (level 0, n = 3), 6.5 Gy x 5 (level 1, n = 12), and 7 Gy x 5 (level 2, n = 9). Primary tumor histologies included non-small cell lung cancer (n = 11), esophageal cancer (n = 4), breast cancer (n = 3), melanoma (n = 3), and others (n = 3). The median tumor/cavity size was 18.5cc (range 9.1 - 57.2cc). The median overall follow-up time is 15.6 months (range 0.5 - 81.6) and median DLT assessment follow-up time is 11.5 months (range 0.5 - 27.3). Four DLTs including intracranial hemorrhage (1) and seizure (3) were observe after a median time of 11 months (range 1-14) in 3/9 patients at dose level 2 and 1/12 patients at dose level 1. Two deaths without clear cause in patients with known DLT were considered possibly related to treatment. Symptomatic RN occurred in 4/9 patients at dose level 2, and 2/12 patients at dose level 1. One patient experienced local tumor failure at 36 months. <h3>Conclusion</h3> The 6.5 Gy x 5 fractions is the maximum tolerated dose and recommended phase 2 dose of 5 fraction radiosurgery for large intact or resected brain metastases. This dose level is well tolerated and local control appears promising, though larger studies are required to further assess treatment efficacy at this dose level.

Hypofractionated Stereotactic Radiation Therapy for Intact Brain Metastases in 5 Daily Fractions: Effect of Dose on Treatment Response

Multileaf collimator (MLC) linear accelerator (Linac)-based hypofractionated stereotactic radiation therapy (HSRT) is increasingly used not only for large brain metastases or those adjacent to critical structures but also for those metastases that would otherwise be considered for single-fraction radiosurgery (SRS). However, data on outcomes in general are limited, and there is a lack of understanding regarding optimal dosing. Our aim was to report mature image-based outcomes for MLC-Linac HSRT with a focus on clinical and dosimetric factors associated with local failure (LF).A total of 220 patients with 334 brain metastases treated with HSRT were identified. All patients were treated using a 5-fraction daily regimen and were followed with clinical evaluation and volumetric magnetic resonance imaging every 2 to 3 months. Overall survival and progression-free survival were calculated using the Kaplan-Meier method, with LF determined using Fine and Gray's competing risk method. Predictive factors were identified using Cox regression multivariate analysis.Median follow-up was 10.8 months. Median size of treated metastasis was 1.9 cm; 60% of metastases were <2 cm in size. The median total dose was 30 Gy in 5 fractions; 36% of the cohort received <30 Gy. The median time to LF and 12-month cumulative incidence of LF was 8.5 months and 23.8%, respectively. Median time to death and 12-month overall survival rates were 11.8 months and 48.2%, respectively. Fifty-two metastases (15.6%) had an adverse radiation effect, of which 32 (9.5%) were symptomatic necrosis. Multivariable analysis identified worse LF in patients who received a total dose of <30 Gy (hazard ratio, 1.62; P = .03), with LF at 6 and 12 months of 13% and 33% for patients treated with <30 Gy versus 5% and 19% for patients treated with >30 Gy. Exploratory analysis demonstrated a dose-response effect observed in all histologic types, including among breast cancer subtypes.Optimal local control is achieved with HSRT of ≥30 Gy in 5 daily fractions, independent of tumor volume and histology, with an acceptable risk of radiation necrosis.