Single-fraction Stereotactic Radiosurgery Research Articles

Radiation necrosis and therapeutic outcomes in patients treated with linear accelerator-based hypofractionated stereotactic radiosurgery for intact intracranial metastases.

Balancing disease control and treatment-related toxicities can be challenging when treating higher-risk brain metastases (BMs) that are larger in size or eloquent anatomical locations. Hypofractionated stereotactic radiosurgery (hfSRS) is expected to offer superior or equal efficacy with lower toxicity profile compared with single-fraction SRS (sfSRS). We report the efficacy and toxicity profiles of hfSRS in a consecutive cohort of patients to support this predicted benefit from hfSRS for high-risk BMs. We retrospectively analysed 185 consecutive individual lesions from 152 patients with intact BMs treated with hfSRS between 1 July 2016 and 31 October 2019 and followed up to 30 April 2022 with serial brain magnetic resonance imaging (MRI). The primary endpoint was the event of radiation necrosis (RN). Local control (LC) rate and distant brain failure (DBF) were reported as secondary outcomes. Kaplan-Meier method was used to report the cumulative incidence of RN and overall survival and the incidence of DBF. Potential risk factors for RN were assessed using univariable Cox regression analysis. The median follow-up was 38.0months, and the median survival post-SRS was 9.5 months. The cumulative incidence rate of RN was 13.2% (95% CI: 7.0-24.7%), and 18.1% of patients with confirmed RN were symptomatic. Higher mean dose delivered to planning target volume (PTV) (HR 1.22, 95% CI: 1.05-1.42, P=0.01), higher mean BED10 (biological equivalent dose assuming a tissue ratio of 10) (HR 1.12, 95% CI: 1.04-1.2, P <0.001), and higher mean BED2 (HR 1.02, 95% CI: 1-1.04, P=0.04) delivered to the lesion was associated with increased risk of RN. LC rate was 86% and the cumulative incidence of DBF was 36% with a median onset of 28.4 months. Our results support the predicted radiobiological benefit of the use of hfSRS in high-risk BMs to limit treatment-related toxicity with low risk for symptomatic RN comparable with lower risk population receiving sfSRS while achieving satisfactory local disease control.

Multimodal Treatments for Brain Metastases from Renal Cell Carcinoma: Results of a Multicentric Retrospective Study

A total of 120 BMRCC patients with a total of 176 lesions treated were evaluated. Patients received surgery plus postoperative HSRS, single-fraction SRS, or hypofractionated SRS (HSRS). Local control (LC), brain distant failure (BDF), overall survival (OS), toxicities, and prognostic factors were assessed. The median follow-up time was 77 months (range 16-235 months). Surgery plus HSRS was performed in 23 (19.2%) cases, along with SRS in 82 (68.3%) and HSRS in 15 (12.5%). Seventy-seven (64.2%) patients received systemic therapy. The main total dose and fractionation used were 20-24 Gy in single fraction or 32-30 Gy in 4-5 daily fractions. Median LC time and 6 month and 1, 2 and 3 year LC rates were nr, 100%, 95.7% ± 1.8%, 93.4% ± 2.4%, and 93.4% ± 2.4%. Median BDF time and 6 month and 1, 2 and 3 year BDF rates were n.r., 11.9% ± 3.1%, 25.1% ± 4.5%, 38.7% ± 5.5%, and 44.4% ± 6.3%, respectively. Median OS time and 6 month and 1, 2 and 3 year OS rates were 16 months (95% CI: 12-22), 80% ± 3.6%, 58.3% ± 4.5%, 30.9% ± 4.3%, and 16.9% ± 3.6, respectively. No severe neurological toxicities occurred. Patients with a favorable/intermediate IMDC score, a higher RCC-GPA score, an early occurrence of BMs from primary diagnosis, absence of EC metastases, and a combined local treatment (surgery plus adjuvant HSRS) had a better outcome. SRS/HSRS is proven to be an effective local treatment for BMRCC. A careful evaluation of prognostic factors is a valid step to manage the optimal therapeutic strategy for BMRCC patients.

Concurrent Administration of Immune Checkpoint Inhibitors and Single Fraction Stereotactic Radiosurgery in Patients With Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma Brain Metastases

Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. As a secondary analysis, recursive partitioning analysis (RPA) was used for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Concurrent SRS and ICI administration. Six hundred fifty-seven patients with 4182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months for the concurrent and nonconcurrent groups, respectively (P=.03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90. In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy: (1) < 12 cm3; (2) 20 cm3 ≥ V12 Gy ≥ 12 cm3; (3) V12 Gy > 20 cm3. In patients with any grade RN, 1-year rates were 3.7% (V12 Gy < 12 cm3), 10.3% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 12.6% (V12 Gy > 20 cm3); the 2-year rates were 7.5% (V12 Gy < 12 cm3), 13.8% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 15.4% (V12 Gy > 20 cm3) (P < 0.001). In patients with any SRN, 1-year rates were 2.4% (V12 Gy < 12 cm3), 8.9% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 10.3% (V12 Gy > 20 cm3); the 2-year rates were 4.4% (V12 Gy < 12 cm3), 12.4% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 13.1% (V12 Gy > 20 cm3; P< 0.001). There were no statistically significant differences in rates of any grade RN or SRN when accounting for therapy timing for all patients and by V12 risk group identified on RPA. The use of SRS and ICI results in a low risk of any grade RN and SRN. This risk is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN.

Radiological Evolution of Fat Graft Used for Optic Neuropexy During Surgery for Parasellar Meningiomas.

Stereotactic radiosurgery (SRS) is an effective adjuvant therapy for residual tumor after subtotal resection of parasellar meningiomas. Fat graft placement between the optic nerve/chiasm and residual tumor (optic neuropexy [OPN]) allows for safe SRS therapy. To evaluate the radiological temporal profile of the fat graft after OPN, immediately after surgery and at 3, 6, and 12 months intervals, to elucidate the optimal time point of adjuvant SRS. A single-center, retrospective, cohort study of 23 patients after surgery for parasellar meningioma was conducted. Fat graft volume and MRI signal ratios were calculated. SRS dosimetric parameters (tumor/optic nerve) were measured at the time of SRS and compared with a hypothetical dosimetric plan based on an early postoperative MRI. Of 23 patients, 6 (26%) had gross total resection and 17 (74%) had subtotal resection. Fat grafts showed a progressive loss of volume and signal ratio over time. Radiosurgery was performed in 14 (82.3%; 8 hypofractionated radiosurgery and 6 single fraction). At 3 months, there is a loss of 46% of the fat volume and degradation of its tissue intensity, decreasing differentiation from tumor and nerve. The hypothetical treatment plan (performed on an early postoperative MRI) showed that single-fraction SRS would have been possible in 6 of the 8 hypofractionated cases. OPN is a technique that can be safely performed after resection of parasellar meningiomas. Because of the reduction of the fat volume and tissue differentiation between fat and tumor/nerves, adjuvant radiosurgery is better performed within the first 3 months after surgery.

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

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

A Comparison of Single Fraction and Multi Fraction Radiosurgery on the Gamma Knife ICON: A Single Institution Review

PurposeBrain metastases are a common development in patients with malignant solid tumors. Stereotactic radiosurgery (SRS) has a long track record of effectively and safely treating these patients, with some limitations to the use of single fraction SRS based on size and volume. In this study, we reviewed outcomes of patients treated using SRS and fractionated SRS (fSRS) to compare predictors and outcomes of those treatments. Methods and MaterialsTwo hundred patients treated with SRS or fSRS for intact brain metastases were included. We tabulated baseline characteristics and performed a logistic regression to identify predictors of fSRS. Cox regression was used to identify predictors of survival. Kaplan-Meier analysis was used to calculate survival, local failure, and distant failure rates. A receiver operating characteristic curve was generated to determine timepoint from planning to treatment associated with local failure. ResultsThe only predictor of fSRS was tumor volume >2.061 cm3. There was no difference in local failure, toxicity, or survival by fractionation of biologically effective dose. Predictors of worse survival were age, extracranial disease, history of whole brain radiation therapy, and volume. Receiver operating characteristic analysis identified 10 days as potential factor in local failure. At 1 year, local control was 96.48 and 76.92% for those patients treated before or after that interval, respectively (P = .0005). ConclusionsFractionated SRS is a safe and effective alternative for patients with larger volume tumors not suitable for single fraction SRS. Care should be taken to treat these patients expeditiously as a delay was shown to affect local control in this study.

Single-fraction stereotactic radiosurgery versus microsurgical resection for the treatment of vestibular schwannoma: a systematic review and meta-analysis

BackgroundVestibular schwannomas are benign tumours for which various treatments are available. We performed a systematic review of prospective controlled trials comparing the patient-relevant benefits and harms of single-fraction stereotactic radiosurgery (sfSRS) with microsurgical resection (MR) in patients with vestibular schwannoma.MethodsWe searched for randomized controlled trials (RCTs) and non-randomized prospective controlled trials in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and study registries (last search: 09/2021) and also screened reference lists of relevant systematic reviews. Manufacturers were asked to provide unpublished data. Eligible studies investigated at least one patient-relevant outcome. We assessed the risk of bias (high or low) at the study and outcome level. If feasible, meta-analyses were performed. We graded the results into different categories (hint, indication, or proof of greater benefit or harm).ResultsWe identified three non-randomized prospective controlled trials of generally low quality with evaluable data on 339 patients with unilateral vestibular schwannoma. There was an indication of greater benefit of sfSRS compared with MR for facial palsy (OR 0.06, 95% CI 0.02–0.21, p < 0.001, 2 studies), hearing function (no pooled estimate available, 2 studies), and length of hospital stay (no pooled estimate available, 2 studies). We found no clinically relevant differences for mortality, vertigo, headaches, tinnitus, balance function, work disability, adverse events, and health-related quality of life.ConclusionsOur systematic review indicates that sfSRS has greater benefits than MR in patients with unilateral vestibular schwannoma. However, it is unclear whether this conclusion still holds after 2 years, as long-term studies are lacking. It is also unclear whether the effects of sfSRS are similar in patients with bilateral vestibular schwannomas. Long-term prospective studies including patients with this condition would therefore be useful.Systematic review registrationThe full (German language) protocol and report (Commission No. N20-03) are available on the institute’s website: www.iqwig.de/en/projects/n20-03.html

Single-fraction SRS and multiple-fraction SRT for brain metastases from colorectal cancer.

Brain metastasis from colorectal cancer (CRC) is rare. Although stereotactic radiotherapy (SRT) and stereotactic radiosurgery (SRS) are effective treatments for brain metastasis, reports on brain metastasis of CRC are limited. This study compared the efficacy of SRT and SRS for the treatment of brain metastases from CRC and analysed the related factors to reveal the specificity CRC-derived brain metastasis. A retrospective analysis of 116 patients with brain metastases from colorectal cancer was performed and included 56 patients in the SRT group and 60 patients in the SRS group. The clinical characteristics of the two groups were analysed, and the local tumour control rate, overall survival time and radiation-induced brain injury were compared between the two groups. The objective response rates of the SRT and SRS groups were 76.8% and 66.7%, respectively, while the local control rates at 6 months were 87.5% and 81.6%, respectively, and no significant differences were observed between the groups (P=0.295). The median overall survival time was 10.3 months for all patients and was 10.9 months in the SRT group and 9.8 months in the SRS group, with no significant difference between the groups (P=0.123). A multivariate analysis showed that the main factors of poor prognosis were low GPA score (P=0.002), KRAS mutation (P=0.035), extracranial metastasis (P=0.005) and no bevacizumab treatment (P=0.001). No significant difference was observed in the incidence of acute and late radiation-induced injury between the two groups. Both SRT and SRS are effective methods for the treatment of CRC-derived brain metastases. The simultaneous use of bevacizumab may be one of the most important factors that affects the survival of these patients.

Role of biological effective dose for prediction of endocrine remission in acromegaly patients treated with stereotactic radiosurgery.

Stereotactic radiosurgery (SRS) can be used in acromegaly patients to achieve endocrine remission. In this study we evaluate the biological effective dose (BED) as a predictor of SRS outcomes for acromegaly. This retrospective, single-center study included patients treated with single-fraction SRS with growth hormone secreting pituitary adenomas and available endocrine follow-up. Kaplan-Meier analysis was used to study endocrine remission, new pituitary deficit, and tumor control. Cox analyses were performed using two models [margin dose (model 2) versus BED (model 1)]. Sixty-seven patients (53.7% male) with a median age of 46.8 years (IQR 21.2) were treated using a median dose of 25Gy (IQR 5), and a median BED of 171.9Gy2.47 (IQR 66.0). Five (7.5%) were treated without stopping antisecretory medication. The cumulative probability of maintained endocrine remission off suppressive medications was 62.5% [47.9-73.0] at 3 years and 76.5% [61.0-85.9] at 5 years. IGF1i > 1.5 was a predictor of treatment failure [Hazard ratio (HR) 0.40 (0.21-0.79) in model 1, p = 0.00783]. Margin dose > 22Gy [HR 2.33 (1.06-5.13), p = 0.03593] or a BED > 170Gy2.47 [HR 2.02 (1.06-3.86), p = 0.03370] were associated with endocrine remission. The cumulative probability of new hypopituitarism after SRS was 36.8% (CI 95% 22.4-45.9) at 3 years and 53.2% (CI 95% 35.6-66) at 5 years. BED or margin dose were not associated with new hypopituitarism. BED is a strong predictor of endocrine remission in patients treated with SRS. Dose planning and optimization of the BED to > 170Gy2.47 give a greater probability of endocrine remission in acromegalic patients.

Radiosurgery fractionation and post-treatment hemorrhage development for intact melanoma brain metastases.

To assess, for intact melanoma brain metastases (MBM), whether single-fraction stereotactic radiosurgery (SRS) versus fractionated stereotactic radiotherapy (fSRT) is associated with a differential risk of post-treatment lesion hemorrhage (HA) development. A single institution retrospective database review identified consecutive patients with previously unresected MBM treated with robotic SRS/fSRT between 2013 and 2021. The presence of lesion HA was determined by multi-disciplinary imaging review. Dosimetric variables were reported as biologically effective doses using an α/β ratio of 2.5 (BED2.5). Statistical analysis was performed using mixed effect logistic regression for post-treatment HA and Cox frailty modeling for local control (LC). The cohort included 48 patients with 226 intact MBM treated with SRS/fSRT. Of lesions without prior HA, 63 of 133 lesions (47.4%) receiving SRS demonstrated evidence of post-treatment HA versus 2 of 24 lesions (8.3%) treated with fSRT (p = 0.01). A larger maximum BED2.5 was observed in lesions developing HA compared to no HA (238.3Gy vs. 211.4Gy; p = 0.022). 12-month LC was 65.7% (95% CI 37.2-87.3%) and 77.5% (95% CI 58.5-91.2%) for lesions demonstrating pre-treatment and post-treatment HA, respectively, with no local failure events observed within 12months for non-hemorrhagic lesions (p < 0.001). We found an increased incidence of post-treatment HA for intact MBM receiving a larger maximum BED2.5, which was significantly higher for single fraction treatments within our cohort. The presence of lesion HA, either pre- or post-treatment, was indicative of inferior LC. Further investigations of optimal dose and fractionation schedules for treatment of MBM in the era of immunotherapy are warranted.

Clinical outcomes of non-small cell lung cancer brain metastases treated with stereotactic radiosurgery and immune checkpoint inhibitors, EGFR tyrosine kinase inhibitors, chemotherapy and immune checkpoint inhibitors, or chemotherapy alone.

Immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used in the systemic management of non-small cell lung cancer (NSCLC) brain metastases (BMs). However, optimizing control of NSCLC BM with stereotactic radiosurgery (SRS) and various systemic therapies remains an area of investigation. Between 2016 and 2019, the authors identified 171 NSCLC BM patients with 646 BMs treated with single-fraction SRS within 3 months of receiving treatment with ICIs (n = 56; 33%), EGFR-TKI (n = 30; 18%), chemotherapy and ICIs (n = 23; 14%), or standard chemotherapy alone (n = 62; 36%). Time-to-event analysis was conducted, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival from SRS. The median follow-up from BM diagnosis was 8.9 months (range 0.3-127 months). The 12-month Kaplan-Meier DIC rates were 37%, 53%, 41%, and 21% (p = 0.047) for the ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy-alone groups, respectively. On multivariate analysis, DIC was improved with EGFR-TKI (HR 0.4, 95% CI 0.3-0.8, p = 0.005) compared with conventional chemotherapy and treatment with SRS before systemic therapy (HR 0.5, 95% CI 0.3-0.9, p = 0.03) compared with after; and LC was improved with SRS before (HR 0.4, 95% CI 0.2-0.9, p = 0.03) or concurrently (HR 0.3, 95% CI 0.1-0.6, p = 0.003) compared with after. No differences in radionecrosis were noted by timing or type of systemic therapy. The authors' analysis showed significant differences in DIC based on receipt of systemic therapy and treatment with SRS before systemic therapy improved DIC. Prospective evaluation of the potential synergism between systemic therapy and SRS in NSCLC BM management is warranted.

Risk Factors for Progression and Toxicity after Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM Multicenter Cohort Study

<h3>Purpose/Objective(s)</h3> Preoperative (preop) stereotactic radiosurgery (SRS) is a feasible alternative to postoperative (postop) SRS with potential benefits in adverse radiation effect (ARE) and meningeal disease (MD) compared to postop SRS. The goal of this study was to determine risk factors for progression and toxicity after preop SRS in an expanded multicenter cohort. <h3>Materials/Methods</h3> Patients with brain metastases (BM) from solid cancers, of which at least 1 lesion was treated with preop SRS and underwent planned resection were included from 6 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included classically radiosensitive or non-solid cancers and prior or planned whole brain radiotherapy (WBRT). SRS dose, fractionation, and interval between preop SRS and surgery was per individual institutional protocol. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Radiographic MD was categorized as nodular (nMD) or classical "sugarcoating" (cMD). <h3>Results</h3> The cohort consisted of 378 patients with 389 preop SRS treated index lesions. Most patients (61.1%) had a single BM, underwent gross total resection (GTR, 95.4%), and had non-small cell lung (NSCLC, 47.9%), breast (16.1%), or melanoma (11.4%) cancer. Median dose was 15 Gy in 1 fraction to a median gross tumor volume (GTV) of 10.1 cc. Median interval between preop SRS and surgery was 2 days. Median cranial imaging follow-up interval was 9.5 months overall and 17.5 months for alive patients. The 2-year cavity local recurrence (LR) rate was 14.5%. Multivariable analysis (MVA) for LR demonstrated subtotal resection (STR, vs. GTR), single fraction SRS (vs. fractionated), larger GTV, gastrointestinal (GI) primary (vs. NSCLC), active systemic disease, and piecemeal resection (vs. en bloc) to be associated with higher risk of LR. Of note, interval between preop SRS and surgery was not significant. The 2-year any grade ARE rate was 7.7%. MVA for ARE demonstrated only larger planning target volume (PTV) margin expansion as associated with higher risk of ARE. The 2-year rate of MD was 5.6%. Most MD (76%) was classical type, with the remainder being nodular type. MVA for MD demonstrated STR (vs. GTR) and breast or melanoma histology (vs. NSCLC) as associated with higher risk of MD. Of note, posterior fossa location and type of surgical resection were not significant. <h3>Conclusion</h3> Preop SRS demonstrates overall excellent rates of cavity LR, ARE, and MD in this expanded multicenter cohort study. We have identified several tumor and treatment factors that are significantly associated with risk of cavity LR, ARE, and MD after treatment with preop SRS. Minimizing likelihood of STR and treating with fractionated preop SRS for larger higher risk tumors may lead to improved outcomes. A randomized trial of preop versus postop SRS is currently being designed (NRG BN012).

Effects of Expansion Size from Gross Tumor Volume to Planning Target Volume on Control Rates and Patterns of Recurrence in Conventionally Fractionated Radiotherapy for WHO Grade I Meningiomas

<h3>Purpose/Objective(s)</h3> In single fraction stereotactic radiosurgery (SRS) for WHO grade I meningiomas, no- or minimal GTV to PTV margin is accepted practice with good outcomes. For complex tumors not eligible for SRS due to size or proximity to critical structures, there has been historical heterogeneity in target volume expansions practices, ranging from margins of a few mm to up to 2 cm. Additional margin is typically added for fractionated treatments to account for setup variability and less precise imaging and setup technique. Larger expansions result in treatment of uninvolved brain parenchyma and organs at risk, which is a concern in patients with expected long survivals. We sought to evaluate whether there is a control difference based on GTV to PTV expansion size in fractionated radiotherapy with either stereotactic or conventional conformal technique. <h3>Materials/Methods</h3> With IRB approval, we identified 87 patients from an institutional database with imaging-defined or WHO grade I meningioma treated with either 3D or IMRT radiation with 5 to 15 mm expansions from GTV (with or without intermediate CTV) or fractionated stereotactic radiotherapy (fSRT) using a system with ≤ 3mm GTV to PTV expansions, treated between 1999 and 2018 with at least 2 years of follow-up. All treatments were delivered using 1.8 Gray (Gy) fractions. Kaplan-Meier estimators were used for local failure-free survival (LFFS), marginal-failure free survival (MFFS) and distant failure-free survival (DFFS) analysis, with censoring occurring at failure event or most recent MRI. Local failure was defined as within the treatment field, marginal within 2 cm, and distant as beyond 2 cm. Patient clinical and demographic characteristics analyzed with χ² testing. <h3>Results</h3> With a median follow-up of 9.0 years, 25 patients (29%) received 3D or IMRT and 62 patients (71%) received fSRT. Doses delivered varied from 50.4-54 Gy, with the majority (71%) receiving 54 Gy. Thirty-two (37%) underwent surgery; 24 were sub-total resections. Total events were low, with 4 local failures (5%), 1 marginal failure (1%) and 1 distant failure (1%). The fSRT and 3D/IMRT groups each had two local failures; 3/4 local failures occurred in areas near critical organs at risk (two in suprasellar region, one in cavernous sinus). Extent of surgical resection was not correlated with risk for local failure. For 3D/IMRT vs fSRT, 5- and 10-year LFFS were 100% vs 98% (p=0.46) and 94% vs 96% (p=0.34), 5- and 10-year MFFS were 100% vs 100% and 100% vs 92% (p=0.004), and 5- and 10-year DFFS were 100% vs 98% at both time points (p=0.65 and p=0.67, respectively). <h3>Conclusion</h3> In this patient cohort, there was no local control benefit to larger GTV to PTV expansions. For patients with tumors not eligible for SRS, fractionated treatment using a rigorous stereotactic workflow with ≤ 3 mm PTV expansions is an effective approach for WHO grade I meningiomas.

Multi-Center Quality of Life Outcomes for Patients with Acoustic Neuromas Treated with a Non-Invasive Stereotactic Radiosurgery Instrument and Linear Accelerator-Based Radiosurgery

<h3>Purpose/Objective(s)</h3> Prior studies have reported favorable local control for patients treated with Gamma Knife (GK) or linear accelerator (LINAC)-based radiosurgery (SRS); however, direct comparison of detailed patient-reported quality of life (QOL) outcomes are lacking. This multi-center retrospective review assessed for differences in QOL outcomes and toxicity profiles after radiotherapy for acoustic neuromas in patients treated with GK and LINAC-based radiosurgery. <h3>Materials/Methods</h3> In this multi-center single institution analysis, we retrospectively reviewed acoustic neuroma cases treated with either GK or LINAC-based SRS between 2008-2017. We compared pre- and post- treatment clinical outcomes including new development of tinnitus, vertigo, gait disturbance, facial palsy, hydrocephalus and audiometric data. We also collected radiographic and dosimetric information including tumor size and dose to cochlea. Descriptive statistics were performed and χ² was utilized to assess for intergroup differences in clinicoradiographic or dosimetric differences. Univariate and multivariate multinomial logistic regression analyses were performed with backward selection at alpha of 0.2 to assess for statistically significant associations with the development of the clinical endpoints described above. <h3>Results</h3> A total of 85 patients were included in our review, 36 in the GK group and 49 in the LINAC-SRS group. 39 patients were male (45.9%) and 46 female (54.1%), 45 were left-sided tumors (52.9%) and 40 right-sided tumors (47.1%). All patients were treated with single-fraction SRS, with a prescription of 12.5 Gy for GK and 12 Gy for LINAC-based SRS. Median follow up was 25 months (median 21 months in GK group, 26 months in LINAC group). On multivariate analysis, there was no significant difference in the development of post-treatment tinnitus, vertigo, gait disturbance, facial palsy, hydrocephalus, change in Gardner Robertson Grade, or change in hearing between the GK and LINAC treatment groups (p> 0.05). Similarly, multivariate analysis did not show tumor size or cochlear dose to be associated with development of specific toxicities between treatment modalities (p>0.05). <h3>Conclusion</h3> This multi-center retrospective review found no significant differences in patient-reported QOL outcomes for patients treated with either Gamma Knife or LINAC-based radiosurgery for acoustic neuromas. This study adds to the body of evidence that both modalities are feasible approaches with similar toxicity profiles for the treatment of acoustic neuromas, and patients can be counselled as such.

Single Fraction vs. Fractionated Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM Multicenter Cohort Study

<h3>Purpose/Objective(s)</h3> Preoperative (preop) stereotactic radiosurgery (SRS) is a feasible alternative to postoperative (postop) SRS with potential benefits in adverse radiation effect (ARE) and meningeal disease compared to postop SRS. Most reported studies of preop SRS utilized single fraction (fx) SRS. The goal of this study was to compare outcomes and toxicity of single fraction preop SRS with fractionated (3-5 fx) preop stereotactic radiotherapy (FSRT). <h3>Materials/Methods</h3> Patients (pts) with brain metastases (BM) from solid cancers, of which at least 1 lesion was treated with preop SRS or FSRT and underwent planned resection were included from 6 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included classically radiosensitive or non-solid cancers and prior or planned whole brain radiotherapy. RT dose, fractionation, and interval between preop RT and surgery was per individual institutional protocol. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Propensity score matched (PSM) analyses were performed. <h3>Results</h3> The cohort included 378 pts with 389 preop RT treated index lesions. Most pts had non-small cell lung (47.9%), breast (16.1%), or melanoma (11.4%) cancer. The majority of pts (61.1%) had a single BM and 95.4% underwent gross total resection (GTR). SRS was used for 328 (84.3%) lesions with FSRT used for 61 (15.7%). Most FSRT (93.4%) was 3 fx, with the remainder being 5 fx. Median prescribed dose for FSRT and SRS was 24 Gy and 15 Gy, respectively. There were baseline imbalances between cohorts. The FSRT cohort had significantly more use of planning target volume (PTV) margin expansion > 1 mm (64% vs. 5.2%), more pts with multiple BM (54% vs. 38%), and larger median gross tumor volume (GTV, 12.3 cc vs. 9.7 cc). In univariate analysis, preop FSRT was associated with significantly lower rate of cavity local recurrence (LR) than SRS (1-year: 2.8% vs. 14.1%, p=0.02). PSM yielded 57 matched pairs. There were no significant residual imbalances in the PSM cohorts. Median imaging FU period was 8 months for both groups. FSRT was associated with significantly lower cavity LR compared with SRS (1-year: 3% vs. 17.9%, p=0.02). There were no differences in ≥ grade 2 ARE (7.4% vs. 4.9%, p=0.34), meningeal disease (2% vs. 4%, p=0.81), or distant brain failure (21.8% vs. 37.4%, p=0.25). No grade 3 - 5 ARE events occurred. Overall survival (OS) was significantly higher with FSRT in PSM analysis as well (1-year: 71.2% vs. 52.1%, p=0.04). <h3>Conclusion</h3> Preop FSRT (3-5 fx) is associated with significantly reduced risk of cavity LR and improved OS compared with preop single fx SRS. Both preop FSRT and SRS show notably low rates of ARE and meningeal disease. Three fx preop FSRT may be a preferred option for neoadjuvant RT of larger or higher risk lesions. Additional confirmatory studies are needed. A randomized trial of preop SRS versus postop SRS is currently being designed (NRG BN012).

Frameless Cobalt60-Based Hypofractionated Stereotactic Radiosurgery (HSRS) for Brain Metastases: Impact of Dose and Volume

<h3>Purpose/Objective(s)</h3> Frameless, gated, image-guided, Cobalt⁶⁰-based hypofractionated stereotactic radiosurgery (Co⁶⁰-HSRS) is a novel technical paradigm in the treatment of brain metastases that allows for both the dosimetric benefits of the Co⁶⁰ based stereotactic radiosurgery (SRS) platform as well as the biologic benefits of fractionation. We report mature local control (LC) and adverse radiation effects (ARE) outcomes following 5 fraction Co⁶⁰-HSRS for intact brain metastases. <h3>Materials/Methods</h3> All patients with intact brain metastases treated with 5-fraction Co⁶⁰-HSRS between 2017-2020 were retrospectively reviewed. Patients were typically selected for HSRS as opposed to single fraction SRS if the metastases were larger (>2cm diameter), were in eloquent areas, or were in proximity to another lesion receiving HSRS. Survival estimates were determined per patient using Kaplan Meier methods, and LC as well as symptomatic ARE rates were determined per lesion using competing risk methods. Univariable competing risk regression using Fine and Gray's methods were performed, and subsequent multivariable (MVA) regression using a backwards step-wise selection technique generated the final adjusted models. <h3>Results</h3> In total 299 metastases in 146 patients were identified. The median clinical and radiologic follow-up was 10.6 (range 0.5-49.9) and 10.7 months (range 0.5-47.6), respectively. The median maximum tumor diameter and volume were 1.7 cm (range, 0.2-3.9 cm) and 2.38 cc (range, 0.004-24.92 cc), respectively. The median total dose and prescription isodose was 27.5 Gy (range, 20-27.5 Gy) in 5 daily fractions and 52% (range, 45%-93%), respectively. The median overall survival (OS) was 12.7 months and the 1-year LC rate was 85%. MVA identified a total dose of 27.5 Gy vs. ≤25 Gy (hazard ratio [HR] 0.59, p = 0.042), and prior chemotherapy exposure (HR 1.99, p = 0.015), as significant predictors of LC. The 1-year ARE rate was 10.8% and the symptomatic ARE rate was 1.8%. MVA identified a gross tumor volume of ≥4.5cc (HR 7.29, p < 0.001) and a mean intra-tumoral dose of ≥39 Gy (HR 3.17, p = 0.034) as significant predictors of symptomatic ARE. <h3>Conclusion</h3> Moderate total doses in 5 daily fractions of Co⁶⁰-HSRS were associated with high rates of LC and a low incidence of symptomatic ARE. A prescription dose of 27.5 Gy was superior with respect to local control versus ≤25 Gy in 5 daily fractions. Target volumes of 4.5cc or larger as well as mean dose >39 Gy, were associated with higher rates of symptomatic necrosis. Further study will help refine the optimal dosimetric constraints for Co⁶⁰-HSRS.

Single-Fraction vs. Fractionated Radiosurgery and the Development of Post-Treatment Hemorrhage for Intact Melanoma Brain Metastases

<h3>Purpose/Objective(s)</h3> To assess whether intracranial stereotactic radiotherapy fractionation is associated with increased risk of post-treatment lesional hemorrhage in patients with intact melanoma brain metastases (MBM). <h3>Materials/Methods</h3> A single institution retrospective review was performed of patients with previously unresected MBM treated with robotic SRS/fSRT between 2013 to 2021. The presence of lesional hemorrhage was determined by multi-disciplinary neuroradiology review of magnetic resonance imaging (MRI). Dosimetric variables were reported as biologically effective doses using an estimated α/β ratio of 2.5 (BED_2.5) for melanoma to permit comparison across varying fractionation schedules. The effect of fractionation and additional prognostic factors on the rate of post-treatment development of hemorrhage was statistically analyzed using logistic regression with random effects to account for interactions between lesions of the same patient. A Cox model was used for local control (LC) with a frailty term to account for dependence between lesions. <h3>Results</h3> The cohort included 48 patients with 226 intact MBM treated with SRS/fSRT. Evidence of hemorrhage prior to treatment was demonstrated in 69 of 226 metastases (30.5%). For lesions without signs of prior hemorrhage, 65 of 157 (41.4%) demonstrated evidence of hemorrhage after radiosurgical treatment. 63 of 133 lesions (47.4%) receiving single-fraction SRS demonstrated evidence of post-treatment hemorrhage versus 2 of 24 lesions (8.3%) treated with fSRT (<i>p=0.01</i>). Treatment factors including lesion size, prescription isodose line, as well as receipt of corticosteroids, targeted, or immune therapy were not predictive of hemorrhage occurrence. A larger maximum BED_2.5 was observed in lesions developing hemorrhage compared to no hemorrhage (mean 238.3 Gy vs. 211.4 Gy; <i>p=0.022</i>). LC at twelve-months was 65.7% (95% CI 37.2-87.3%) and 77.5% (95% CI 58.5-91.2%) for lesions demonstrating pre-treatment and post-treatment hemorrhage, respectively, with no local failure events observed in non-hemorrhagic lesions (<i>p=<0.001</i>). <h3>Conclusion</h3> Intact MBM without prior evidence of hemorrhage receiving single-fraction SRS were associated with an increased incidence of post-treatment hemorrhage when compared to those treated with fractionated stereotactic radiotherapy. The presence of lesion hemorrhage, either pre- or post-treatment, was associated with inferior local control. Post-treatment hemorrhage was correlated with a larger maximum BED_2.5. Further investigations of the clinical impact of lesional hemorrhage, factors influencing lesion control, as well as optimal dose and fractionation schedules for treatment of MBM in the era of immunotherapy are warranted.

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.

P11.11.B Stereotactic radiosurgery for brain metastases;outcome and prognostic factors in patients treated with single-fraction and multiple-fractions

Abstract Background Stereotactic radiosurgery (SRS) is preferred to whole brain radiotherapy (WBRT) for the treatment of patients with a limited number of brain metastases, both as primary treatment and after surgery. SRS can be delivered in a single fraction (SF) or in multiple fractions (MF) depending on tumor size and location. The aim of this single-center retrospective study was to evaluate intracranial control and overall survival (OS) in patients who received SF and MF SRS for brain metastases. Material and Methods All patients treated with primary SRS for brain metastases at Aarhus University Hospital between 2015 and 2020 were identified. Independent of undergoing surgery, SF SRS (20 Gy) was administered for targets (gross tumor volume) &amp;lt;2 cm in diameter and MF SRS (24-27 Gy in 3 fractions) for targets &amp;gt;2 cm. SRS was not combined with WBRT. Treatment response was evaluated by 3-monthly MRI-scan. To evaluate intracranial control, first events were scored as local-only failure (tumor progression at the SRS treatment site), distant failure (tumor progression not at the SRS site), and combined failure (local and distant failure). Actuarial incidence of local failure (local-only and combined) and OS were estimated using the Kaplan-Meier method. To analyze the association of SF and MF SRS with local failure and OS, multivariable Cox regression analyses were used. Results The consecutive cohort consisted of 196 patients treated for 275 brain metastases. The most frequent primary disease was non-small cell lung cancer (NSCLC n=96), followed by renal cell carcinoma (n=26) and breast cancer (n=22). SRS was delivered to 1 (n=133), 2 (n=49), 3 (n=12), and 4 (n=2) targets per patient. SF and MF SRS was used in 99 (51%) and 97 (49%) patients, respectively. In 40 patients, SRS was administered after surgery (SF n=7, MF n=33). At a median (range) follow-up of 10 (0-93) months, 111 (57%) patients had intracranial progression, and 159 (81%) patients died. Local-only/distant/combined failure rate was 23 and 42%/59 and 35%/18 and 23%, in SF and MF SRS respectively. The median time to local failure was respective 9.0 (95% CI 5.4-12.6) and 6.0 (95% CI 5.0-7.0) months in the SF and MF SRS group. SF SRS and surgery were independently associated with a longer time to local failure. Salvage WBRT, SRS, and re-operation were performed in respective 36, 13, and 26 patients. Histopathological radiation necrosis was observed in 5 patients. All patients with necrosis had a primary diagnosis of NSCLC, and 4/5 patients were treated with SF SRS. For the total group, the median OS was 10.0 (95% CI 8.0 - 12.0) months. PS&amp;lt;2, surgery, stable extracranial disease and SF SRS were associated with a longer survival. Conclusion MF SRS was associated with a higher rate of and shorter time to local failure, and was a poor prognostic factor for survival, which is in line with the selection of patients with more unfavorable brain metastases for this treatment.

P11.45.B Improved overall survival following Stereotactic Radiosurgery for brain metastases - a single institution experience

Abstract Background Brain metastases are increasingly common due to longer survival associated with advancements in treatment. Approximately 40% of cancer patients are diagnosed with brain metastases at some point during their disease. Stereotactic radiosurgery (SRS) avoids the neuro-cognitive toxicity associated with whole brain radiotherapy and has been increasingly offered as a treatment alternative for brain metastases. Combined with developments in systemic treatments, this approach has resulted in improved overall survival (OS). This study reviewed patients treated with single fraction SRS at our institution with a primary endpoint of overall survival. Material and Methods A retrospective review determined overall survival for 237 patients who received single fraction SRS for 451 brain metastases from solid tumours between 1st January 2017 and 31st December 2021. Primary tumour sites were classified as breast, kidney, colorectal, melanoma, lung or other. SPSS v.27 was used for Kaplan Meier OS determination. The median follow up was 10.3 months. Cox regression analysis assessed the association between Gross Tumour Volume (GTV) and OS. Results In this patient cohort, 60% (N=142) were female and 40% (N=95) were male, with a median age of 63 [32-85]. 63.7% (N = 151) had a solitary metastasis. Patients received a single fraction of 15, 17.5 or 20 Gy (prescribed to 80% isodose) dependent on the planning target volume (PTV) size and whether it was initial treatment or re-treatment. 71% of all patients were alive at 6 months with median OS of 12.0 months [10.6-13.4]. Primary tumour site significantly affected OS (Log rank, Chi squared 15.656, p0.008) with breast cancer patients (N=58) surviving longest with a median OS 16.0 months [13.6-18.4] followed by melanoma median OS 15.0 months [7.6-22.4], kidney cancer patients (N = 24) median OS 12.0 months [8.3-15.7] and lung patients (N=87) median OS 10.0 months [8.9-11.3]. The lowest median OS was for colorectal patients at 7.0 months [1.4-12.6]. However, considering the small sample size, N = 15, more data is needed to confirm the significance. The larger the GTV volume the lower the survival time (Chi squared 8.692, p 0.003). Conclusion 71% of patients had an OS of 6.0 months or more with a median of 12.0 months. As expected, primary tumour site has a significant impact on OS, with breast cancer patients living longest. In addition, increasing GTV size is associated with significantly worse survival. Given the improved survival for these patients, the avoidance of neuro cognitive decline remains of paramount importance and outcomes for these patients need to be reported in future work.