Fraction Stereotactic Radiosurgery Research Articles

Pattern of recurrence after stereotactic body radiotherapy of nodal lesions: a single-institution analysis.

Stereotactic body radiotherapy (SBRT) and/or single fraction stereotactic body radiosurgery (SRS) are effective treatment options for the treatment of oligometastatic disease of lymph nodes. Despite the encouraging local control rate, progression-free survival remains unfair due to relapses that might occur in the same district or at other sites. The recurrence pattern analysis after nodal local ablative RT (laRT) in oligometastatic patients is presented in this study. The pattern of failure of patients with nodal metastases who were recruited and treated with SBRT in the Destroy-1 or SRS in the Destroy-2 trials was investigated in this single-institution, retrospective analysis. The different relapsed sites following laRT were recorded. Data on 190 patients who received SBRT or SRS on 269 nodal lesions were reviewed. A relapse rate of 57.2% (154 out of 269 nodal lesions) was registered. The pattern of failure was distant in 88 (57.4%) and loco-regional in 66 (42.6%) patients, respectively. The most frequent primary malignancies among patients experiencing loco-regional failure were genitourinary and gynaecological cancers. Furthermore, the predominant site of loco-regional relapse (62%) was the pelvic area. Only 26% of locoregional relapses occurred contra laterally, with 74% occurring ipsilaterally. The recurrence rates after laRT for nodal disease were more frequent in distant regions compared to locoregional sites. The most common scenarios for locoregional relapse appear to be genitourinary cancer and the pelvic site. In addition, recurrences often occur in the same nodal station or in a nodal station contiguous to the irradiated nodal site. Local ablative radiotherapy is an effective treatment in managing nodal oligometastasis. Despite the high local control rate, the progression free survival remains dismal with recurrences that can occur both loco-regionally or at distance. To understand the pattern of failure could aid the physicians to choose the best treatment strategy. This is the first study that reports the recurrence pattern of a significant number of nodal lesions treated with laRT.

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

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

Radiation-Induced Sensorineural Hearing Loss and Potential Management

The cochlear apparatus is one of the major organs at risk when considering radiation therapy (RT) for brain, head, and neck tumors. Radiation oncologists currently consider mean dose constraints of <35 Gy for conventionally fractioned radiation therapy (RT), <4 Gy for single fraction stereotactic radiosurgery, and <17.1 or 25 Gy for 3- or 5-fraction stereotactic radiosurgery, respectively, as the standard of care. Indeed, dose adjustments are made in the setting of concurrent platinum-based chemotherapy or when prioritizing tumor coverage during treatment planning. Despite guidelines, in many patients, RT to the cochlea may still cause sensorineural hearing loss through progressive degeneration and ossification of the inner ear. There are several audiologic and otolaryngologic interventions for incident RT-induced hearing loss, including hearing aids, cochlear implants, or, in the context of vestibular schwannoma due to neurofibromatosis type 2, auditory brain stem implantation. Cochlear implants are the most effective at restoring hearing and improving quality of life for those with an intact cochlear nerve. An early multidisciplinary approach is essential to optimally manage RT-induced hearing loss, and this topic discussion serves as a guide for radiation oncologists on cochlear dosimetric considerations as well as how to address potential RT-induced adverse effects.

RADT-05. SINGLE VERSUS MULTI-FRACTION STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: RATES OF LOCAL PROGRESSION AND NECROSIS

Abstract PURPOSE For large brain metastases, it is unknown whether single fraction stereotactic radiosurgery (sSRS) or multi-fraction stereotactic radiosurgery (fSRS) is optimal. We aimed to compare rates of local progression and necrosis between sSRS and fSRS for large brain metastases. METHODS Patients with intact or resected brain metastases with a target volume ≥ 4.2 cc (corresponding to a diameter ≥ 2 cm) treated with Gamma Knife (GK) or linear accelerator-based SRS from 2014-2022 were included in this retrospective review. RESULTS A total of 343 large brain metastases in 276 patients were included; 171 lesions were treated with sSRS (96% with GK) and 172 lesions with fSRS (100% with linear accelerator). Median lesion volume was 19.8 cc and 8.4 cc for fSRS and sSRS, respectively. Resection was performed prior to SRS in 228 (66%), with the remaining 115 metastases treated intact. There was no difference in rate of local progression between sSRS versus fSRS, or between resected versus intact targets (p &amp;gt;0.8 for both). Cumulative incidence of local progression (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 24% and 30%, respectively, compared to 22% and 34% for fSRS. FSRS was associated with significantly higher rates of necrosis than sSRS (HR 5.58, 2.38-13.08, p &amp;lt; 0.001). This association remained significant after controlling for target volume. Cumulative incidence of necrosis (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 1% and 3%, respectively, compared to 10% and 18% for fSRS. Necrosis rates were significantly higher with fSRS for both intact and resected targets (P &amp;lt; 0.02 for both). CONCLUSION While local control for large resected or intact brain metastases appears similar after sSRS or fSRS, this retrospective study shows higher rates of necrosis after fSRS. Prospective validation is needed.

Single fraction and hypofractionated radiosurgery for perioptic meningiomas-tumor control and visual outcomes: a systematic review and meta-analysis.

Perioptic meningiomas, defined as those that are less than 3mm from the optic apparatus, are challenging to treat with stereotactic radiosurgery (SRS). Tumor control must be weighed against the risk of radiation-induced optic neuropathy (RION), as both tumor progression and RION can lead to visual decline. We performed a systematic review and meta-analysis of single fraction SRS and hypofractionated radiosurgery (hfRS) for perioptic meningiomas, evaluating tumor control and visual preservation rates. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we reviewed articles published between 1968 and December 8, 2022. We retained 5 studies reporting 865 patients, 438 cases treated in single fraction, while 427 with hfRS. For single fraction SRS, the overall rate of tumor control was 95.1%, with actuarial rates at 5 and 10years of 96% and 89%, respectively; tumor progression was 7.7%. The rate of visual stability was 90.4%, including visual improvement in 29.3%. The rate of visual decline was 9.6%, including blindness in 1.2%. For hfRS, the overall rate of tumor control was 95.6% (range 92.1-99.1, p < 0.001); tumor progression was 4.4% (range 0.9-7.9, p = 0.01). Overall rate of visual stability was 94.9% (range 90.9-98.9, p < 0.001), including visual improvement in 22.7% (range 5.0-40.3, p = 0.01); visual decline was 5.1% (range 1.1-9.1, p = 0.013). SRS is an effective and safe treatment option for perioptic meningiomas. Both hypofractionated regimens and single fraction SRS can be considered.

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

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

Fractionated Radiosurgery in Large Volume Relapsed Glioblastoma Multiforme

Relapse is part of the natural history in glioblastoma (GBM) and there are limited advances in surgical, alternating electric field therapy (TTF), chemotherapy (CTX), immunotherapy or radiotherapeutic treatments. Radiosurgery (SRS) and Fractionated Stereotactic Radiosurgery (FSRS) may be an option, but remains controversial. We performed a review of our patients with recurrent large volume glioblastoma treated with FSRS over the last 5 years. Since January 2017 to December 2021, we reviewed our experience with large volume FSRS for the treatment of selected patients with large volume GBM recurrence. Indications and treatment planning were done according RANO criteria MR images. Overall survival (OS) and progression-free survival (PFS) after salvage FSRS were the primary endpoints evaluated. Response to FSRS was assessed with clinical evaluation and using brain MR. A total of 15 patients with GBM recurrence were treated in our institution after surgery plus adjuvant radio-chemotherapy treatment with Stupp regimen. Median age was 58 (53-74) years old. Prescription dose was 24 Gy in 4 fractions in consecutive days. Selected patients for FSRS had a good PS with large volume relapse and edema. The target volume (CTV) was the enhanced volume in MR T2 classically known has edema and the relapsed T1 volume with gadolinium uptake. The median PTV was 118.5 cc (50-244cc). 33% of the patients received concurrent chemotherapy or biological therapy with or after FSRS. No patient developed G3 symptomatic adverse radiation effect. Median follow-up was 28.6 (10-82) months from diagnosis. PFS after salvage FSRS was 11 (4-55) months. Median overall survival was 12.4 months after FSRS. Our experience and results suggest that reirradiation provides encouraging disease control and survival rates in GBM relapsed patients. The large volume FSRS associated or not with systemic treatment had good tolerance and can improve survival of patients with relapsed large volume GBM. Randomized controlled trials are needed to establish the optimal management strategy for recurrent GBM.

Clinical Outcomes Following Postoperative Cavity Stereotactic Radiosurgery for Brain Metastases

We evaluated outcomes of patients with brain metastases (BM) treated with surgical resection and postoperative cavity stereotactic radiosurgery (SRS) to identify which baseline characteristics and treatment factors may increase risk for local recurrence (LR). From June 2017 to December 2021, 68 patients underwent surgical resection for BM followed by single-fraction SRS (n = 15) or fractionated SRS (FSRS) in 3 (n = 24) or 5 (n = 29) fractions to the postoperative cavity using frameless LINAC-based technique. Patients treated with surgery alone or surgery with postoperative whole brain radiotherapy (WBRT) were excluded. Median prescription doses were 1600 cGy (range: 1440-1875) in 1 fraction, 2400 cGy (range: 2100-2700) in 3 fractions, and 3000 cGy (range: 2500-3000) in 5 fractions. Local control (LC) and overall survival (OS) were estimated by the Kaplan-Meier method. Cox proportional hazards models were used to compare groups. Median follow-up was 19.5 months (IQR: 9.0-34.7). Median patient age was 62.5 years (range: 24-80), and 38 (55.9%) patients were male. Primary tumors were lung (n = 29), including NSCLC (n = 28) and SCLC (n = 1), melanoma (n = 12), breast (n = 11), and other (n = 16). Median preoperative tumor maximal dimension was 3.5cm (range: 1.1-6.3). Median planning treatment volume (PTV) was larger in the FSRS group (26.2cc (range: 6.5-151.8)) than in the SRS group (7.7cc (range: 1.1-11.5)) (p<0.001). Median number of concurrently treated intact lesions was 0 (range: 0-13). Median time from surgery to SRS was 32 days (range: 14-77). Forty-eight (70.6%) patients were treated with immunotherapy or targeted therapy. Median OS was 22.3 months (95% CI: 14.4-30.9). The 1-year and 2-year OS rates were 70% and 48%, respectively. The 1-year and 2-year LC rates were 86% and 73%, respectively. Median time to LR was 8.4 months (95% CI: 4.4-11.0). Among the 14 patients with LR, 11 had undergone salvage therapy at last follow-up which included repeat SRS (n = 4), WBRT (n = 3), palliative local radiotherapy (n = 2), surgery followed by repeat SRS (n = 1), and systemic therapy (n = 1). Eleven (16.2%) patients ultimately underwent WBRT post-SRS for local and/or distant failure. No difference in LC was observed based on primary tumor, time interval between resection and SRS, PTV volume, prescription dose, or fractionation regimen (SRS v. FSRS). However, all LR in the 3-fraction group occurred in patients who received less than 2700 cGy. Favorable LC and OS outcomes were observed following postoperative cavity SRS for resected BM in a modern cohort with a large percentage of patients receiving immunotherapy or targeted therapy. No prognostic factors were identified for LC which may be attributable to the cohort size and small number of events observed. However, our findings suggest that patients who undergo 3-fraction FSRS should be treated to a total dose of 2700 cGy to maximize LC.

Risk Factors Associated with Development of Peritumoral Edema Following Stereotactic Radiosurgery and Radiotherapy for Intracranial Meningioma

Peritumoral edema (PTE) is a potential adverse effect following radiotherapy for intracranial meningioma. The purpose of this study is to identify which baseline factors may increase risk for PTE. A retrospective chart review was conducted of 431 patients who underwent primary radiotherapy to 480 radiographically-defined intracranial meningiomas between January 2008 and December 2021 within an integrated health care system. Patients with prior surgical management were excluded. Patients were treated with frameless LINAC-based image-guided single fraction stereotactic radiosurgery (SRS) (32.9%), 5 fraction SRS (FSRS) (30.8%), or fractionated stereotactic radiotherapy (FSRT) (36.3%). Pre- and post-radiotherapy MRI studies were reviewed to evaluate for PTE following treatment. An event was defined as new or worsening PTE compared to pre-radiotherapy imaging or development of new symptoms post-radiotherapy. Univariate and stepwise logistics regression analyses were performed to compare the risk of PTE between groups. Median follow-up was 85.8 months (IQR: 49.4-125.4). Median patient age was 66 years (IQR: 56-73). Patients treated with SRS (median age: 61 years) were younger than those treated with FSRS/FSRT (median age: 68 years) (p<0.001). Lesions treated with SRS (median volume: 1.33cc) were smaller than those treated with FSRS/FSRT (median volume: 6.36cc) (p<0.001). For all-comers, 68 (14.2%) lesions developed any PTE, and 27 (5.6%) developed symptomatic PTE (SPTE). Of these, 4 patients developed symptoms post-treatment without radiographic evidence of new or worsening PTE. Incidence of PTE/SPTE by site was as follows: base of skull (BOS): 10.3%/6.1%, convexity: 22.7%/7.6%, falcine: 17.6%/4.1%, parasagittal: 27.8%/8.3%, posterior fossa/tentorium 7.0%/0.0%. Incidence of PTE/SPTE by technique was as follows: SRS: 6.3%/3.8%, FSRS: 20.9%/7.4%, FSRT: 15.5%/5.7%. On univariate analysis, age >65 (OR = 2.17 (95% CI: 1.26-3.77) p = 0.006), tumor volume (OR = 1.05 (1.02-1.08), p = 0.003), pre-treatment PTE (OR = 6.82 (95% CI: 3.59-12.94) p<0.001), and convexity/falcine/parasagittal (CFPS) location (OR = 2.52 (95% CI: 1.49-4.23) p<0.001) were associated with increased incidence of PTE. On multivariate analysis, age >65 (OR = 1.91 (95% CI: 1.05-3.45) p<0.03), tumor volume (OR = 1.04 (95% CI: 1.00-1.08) p = 0.03), pre-treatment PTE (OR = 4.64 (95% CI: 2.33-9.24) p<0.001), and CFPS location (OR = 2.53 (95% CI: 1.41-4.52) p = 0.002) were associated with increased incidence of PTE. Two patients with PTE underwent resection for local failure which revealed atypical meningioma. Age >65, larger tumor volume, presence of pre-treatment PTE, and CFPS location were associated with increased incidence of PTE following radiotherapy. Patients with these risk factors should be counseled regarding post-treatment effects. Infrequently, PTE following treatment may be an indicator of higher-grade meningioma.

Symptomatic Posttreatment Edema after Stereotactic Radiotherapy for Intracranial Meningiomas: Patterns and Predictive Factors

Symptomatic posttreatment edema (SPTE) is a complication that may develop after radiotherapy for intracranial meningiomas. Our study aims at reviewing rates of SPTE in a large cohort of a single institution and identifying possible predictive factors. We retrospectively analyzed data of 293 patients with 304 intracranial meningiomas irradiated at our institution between 2005 and 2018. We evaluated rates of SPTE and investigated numerous factors by univariate and multivariate analysis. Kaplan Meier analysis was used for estimation of actuarial local control and overall survival. Median age was 60 years. Meningiomas were treated with fractionated stereotactic radiation therapy (70%), single fraction stereotactic radiosurgery (24%) or fractionated stereotactic radiosurgery (6%). Median imaging follow-up was 60 months, actuarial 10-year local control rate for patients with grade 1 meningiomas who received radiotherapy as definitive treatment was 99%. Local control at 5 years was 94% for grade 1 meningioma, 57% and 53% for grade 2 and 3 respectively. Sixteen patients (5.5%) developed SPTE, median time to onset was 3 months (range, 1-26 months). On univariate analysis, age > 60 years (p > 0.03), pre-treatment peritumoral edema (p = 0.014), medline location (p = 0.018), tumor size > 30 mm (p = 0.015) and grade 2 histology (p = 0.03) were predictive of SPTE. On multivariate analysis, only tumor location and size remained statistically significant. Based on our results, patients at high risk of SPTE can be identified based on patient and tumor characteristics. The best treatment technique in high-risk patients is yet to be defined.

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

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

Hypofractionated Stereotactic Radiotherapy vs. Single Fraction Stereotactic Radiosurgery to the Resection Cavity of Brain Metastases after Surgical Resection (SATURNUS trial): A Prospective, Randomized Phase III Trial

The brain is a common site for metastases. Resection of large or symptomatic metastases is followed by stereotactic radiotherapy to prevent local recurrence. The optimal fractionation scheme is subject of ongoing research. Supported by emerging retrospective data, we hypothesize that hypofractionated stereotactic radiotherapy (HFSRT) is superior to single-fraction stereotactic radiosurgery (SRS) in terms of local control (LC). We designed the SATURNUS trial to prospectively demonstrate the superiority of HFSRT over SRS after resection of brain metastases in terms of LC. The SATURNUS trial is a prospective, randomized phase III trial, currently recruiting patients at a single institution. Patients are 1:1 allocated to HFSRT or SRS using permuted block randomization. Affiliation to the treatment arm is solely blinded to the neuroradiologist assessing therapy response. HFSRT will be delivered with 6 - 7 x 5 Gy and SRS with 1 x 12-20 Gy, prescribed to the surrounding isodose, depending on cavity size and proximity to structures at risk. For SRS, doses do not exceed the maximum doses according to RTOG 90-05. Case number calculation was based on own institutional data on HFSRT (mean LC rate of 88% at 12 months) and data from large phase III trials on SRS (pooled mean LC rate of 66% at 12 months). Using a Chi-squared test of equal proportions (odds ratio = 1), setting test significance level (α) to 0.05, and allocating an equal number of patients to both treatment arms, 114 patients are needed to detect the superiority of HFSRT in terms of LC at 12 months (primary endpoint) with a power of at least 80%. Estimating a dropout rate of 10%, the case number was set to 126. The trial was registered with clinicaltrials.gov (NCT05160818). The first patient was enrolled in May 2021 and recruitment is ongoing. Patients with up to three resected brain metastases are considered for study participation. Further eligibility criteria are histologically confirmed solid tumor disease, resection cavity diameter ≤ 4 cm, consent to perform adjuvant radiotherapy by an interdisciplinary tumor board, completed wound healing, resection within the last six weeks at the time of study inclusion, age ≥ 18 years, KPS ≥ 60%, adequate contraceptive measures for fertile women / men and written informed consent. Patients are followed up clinically and with MRI at 6 weeks and 3, 6, 9 and 12 months after treatment. LC is assessed according to RANO-BM. Toxicity (CTCAE v4.03) is assessed as a secondary endpoint. The rather broad dose corridors allowed within the trial do justice to clinical reality, however, may represent a limitation of the trial. They are therefore addressed with a predefined subgroup analysis, as will be cavity size, among others. Participation of further study centers is desired. To the best of our knowledge, the SATURNUS trial is the only randomized phase III trial adequately powered to detect the superiority of HFSRT over SRS with regard to LC for resected brain metastases. To be determined. To be determined.

Efficacy and Safety of Multifraction Stereotactic Radiation Therapy with Volumetric Modulated Arc Therapy Technique for Multiple Brain Metastases

Multifraction stereotactic radiotherapy (MF-SRT) with volumetric modulated arc therapy (VMAT) is the standard treatment option for patients with multiple brain metastases. VMAT has superior physical accessibility and economic accessibility compared with advanced radiotherapy technologies such as Tomo or Proton radiotherapy. However, existing studies has mainly focused on comparing the dosimetric parameters between distinct radiotherapy techniques. Moreover, single fraction stereotactic radiosurgery is preferentially recommended for treatment of brain metastases with maximum diameter <2cm compared with MF-SRT. There is a lack of clinical results of its efficacy and subgroup analyses according to diameter. Thus, we first report the detailed analysis of clinical results of SRT using VMAT for brain metastases. This study is a retrospective analysis of SRT for multiple brain metastasis using VMAT. The clinical efficacy of VMAT was evaluated by local control (LC) in 6-months, 1-year, and 2-year. A total of 63 patients with 214 brain metastases were enrolled. The most common fractionation schemes were 40 Gy/8F and 48 Gy/12F. In all, LC rates at 6-month, 1-year, and 2-year were 95.5%, 90.6%, and 76.8%, respectively. Using univariate and multivariate analyses according to stratification factors including maximum diameter, GTV volume, dose per fraction, fractions, inner structure, and BED (α/β = 10), we found that no factors were associated with 6-month LC, 1-year LC, and 2-year LC. 1-year LC rates for maximum diameter ≥1 and <2, ≥2 and <3, and ≥3 cm were 89.2%, 90.7%, and 95.7%, respectively. The 1-year LC rates for tumors with GTV <3, ≥3 and <5, ≥5 and <10, and ≥10 cc were 87.0%, 91.7%, 94.7%, and 96.6%, respectively. Interestingly, 1year-LC in GTV ≥3 cc tends to higher than those in GTV <3 cc, but there was no significant difference (94.4% vs 87%, P = 0.162). Brain radionecrosis (RN) was the most significant toxicity occurring in 10 (4.7%) out of the 214 treated brain metastases. Among 6 patients with RN, 4 (66.7%) had been treated with tyrosine kinase inhibitors. The use of MF-SRT with VMAT for multiple brain metastases showed a comparable clinical efficacy to other techniques described in the literature. And the LC rate for maximum diameter <2cm treated with MF-SRT VMAT was comparable to single fraction stereotactic radiosurgery as previously reported. The treatment-related toxicity was acceptable.

Immune Checkpoint Inhibition and Single Fraction Stereotactic Radiosurgery in Non-Small Cell Lung Cancer Brain Metastases: An International Multicenter Study of 395 Patients

Brain metastases most commonly arise from non-small cell lung cancer (NSCLC). In recent years, immune checkpoint inhibitors (ICI) have demonstrated improvements in overall survival (OS) in NSCLC. However, concerns remain about the risk of radiation necrosis (RN) when ICI are administered with stereotactic radiosurgery (SRS). Logistic regression was used to evaluate prognostic factors associated with the development of any grade RN and symptomatic RN. Cumulative incidence of RN was evaluated using competing risks analysis and the Fine and Gray model, where the null hypothesis was rejected for p < 0.05. There were 395 patients with 2,513 brain metastases treated across 11 international institutions included in the analysis. The median follow-up was 14.2 months. Median patient age was 67 years (Interquartile Range [IQR]: 61-73), 53.4% were male, the median Karnofsky Performance Status was 80 (IQR: 80-90), and 88.6% has active extracranial disease at the time of SRS. The median margin dose was 19 Gy (IQR: 18-20), 97.5% of patients were treated on the Gamma Knife ®, 3.8% underwent prior whole brain radiation therapy (WBRT). The median V12 Gy was 5.2 cm3 and 36.5% of patients had a V12 Gy ≥ 10 cm3, anti-PD-1 agents were administered in 91.6% of patients. A V12 Gy ³ 10 cm3 was associated with an increased risk of developing any grade RN; odds ratio (OR): 2.12, p = 0.04 and OR: 2.18; p = 0.03 on univariable and multivariable analysis, respectively. Similarly, a V12 Gy ≥ 10 cm3 was associated with an increased risk of developing symptomatic RN; OR: 3.80, p = 0.003 and OR: 3.95; p = 0.003 on univariable and multivariable analysis, respectively. Receipt of concurrent ICI and prior WBRT were not statistically significant. At 1-year, the cumulative incidence of any grade and symptomatic RN was 4.8% and 3.8%, respectively. The cumulative incidence of any grade RN was 3.8% vs. 5.3% for the concurrent and non-concurrent groups at 1-year, respectively (p = 0.35). The cumulative incidence of symptomatic RN was 3.8% vs. 3.6% for the concurrent and non-concurrent groups at 1-year, respectively (p = 0.95). The risk of any grade and symptomatic RN following SRS and ICI administration for NSCLC brain metastases increases as the V12 Gy exceeds 10 cm3. Concurrent ICI and SRS does not appear to increase this risk. Radiosurgical planning techniques should aim to minimize the V12 Gy.

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

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

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

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

INCIDENCE AND PREDICTORS OF CLINICALLY SIGNIfiCANT ACUTE AND LATE TREATMENT-RELATED TOXICITY AFTER STEREOTACTIC RADIOSURGERY IN 4 OR MORE BRAIN METASTASES

Abstract AIMS Selected patients with multiple brain metastases can benefit from stereotactic radiosurgery (SRS). Brain V12 (total brain volume receiving 12Gy including target) can predict for late toxicity in single target benign disease, however their value remains uncertain for multiple brain metastases. We report the incidence and evaluate predictors of toxicity in patients with 4 or more brain metastases treated with single fraction SRS. METHOD 226 patients with 2160 treated metastases from 2014-21 were retrospectively studied. Severe acute toxicity, and symptomatic late toxicity (new/progressive neurological symptoms ≥ 3 months post SRS) with MRI changes suggestive of treatment-effect were analysed. Kaplan-Meier method and cumulative incidence function was used to assess survival and toxicity respectively. RESULTS Median number of metastases per patient was 6 (range 4-41) and median V12 was 11.3cc (range 1.5- 45.2cc). Median overall survival (mos.) was 7.6 months. Absolute incidence of acute grade 3/4 cerebral oedema/haemorrhage was 4.9%. The subgroup developing late SRS-related toxicity (16 patients) had a higher mos. than those without toxicity (25mos vs 5 mos., p &amp;lt;0.002). 9/16 (56%) patients developed Grade 3 or 4 toxicity. 82/226 patients survived &amp;gt;12 months and cumulative incidence function of symptomatic SRS-related late toxicity in this group was 4% at 1 year and 9.5% at 2 years. CONCLUSIONS Within the limits of data available a brain V12 value did not meaningfully predict for late SRS related toxicity in patients with multiple brain metastases. The cumulative incidence of clinically relevant late toxicity remains &amp;lt;10% at 2 years despite accepting a high median V12 to treat these patients.

Hypofractionated stereotactic radiotherapy (HFSRT) versus single fraction stereotactic radiosurgery (SRS) to the resection cavity of brain metastases after surgical resection (SATURNUS): study protocol for a randomized phase III trial

BackgroundThe brain is a common site for cancer metastases. In case of large and/or symptomatic brain metastases, neurosurgical resection is performed. Adjuvant radiotherapy is a standard procedure to minimize the risk of local recurrence and is increasingly performed as local stereotactic radiotherapy to the resection cavity. Both hypofractionated stereotactic radiotherapy (HFSRT) and single fraction stereotactic radiosurgery (SRS) can be applied in this case. Although adjuvant stereotactic radiotherapy to the resection cavity is widely used in clinical routine and recommended in international guidelines, the optimal fractionation scheme still remains unclear. The SATURNUS trial prospectively compares adjuvant HFSRT with SRS and seeks to detect the superiority of HFSRT over SRS in terms of local tumor control.MethodsIn this single center two-armed randomized phase III trial, adjuvant radiotherapy to the resection cavity of brain metastases with HFSRT (6 – 7 × 5 Gy prescribed to the surrounding isodose) is compared to SRS (1 × 12–20 Gy prescribed to the surrounding isodose). Patients are randomized 1:1 into the two different treatment arms. The primary endpoint of the trial is local control at the resected site at 12 months. The trial is based on the hypothesis that HFSRT is superior to SRS in terms of local tumor control.DiscussionAlthough adjuvant stereotactic radiotherapy after resection of brain metastases is considered standard of care treatment, there is a need for further prospective research to determine the optimal fractionation scheme. To the best of our knowledge, the SATURNUS study is the only randomized phase III study comparing different regimes of postoperative stereotactic radiotherapy to the resection cavity adequately powered to detect the superiority of HFSRT regarding local control.Trial registrationThe study was retrospectively registered with ClinicalTrials.gov, number NCT05160818, on December 16, 2021. The trial registry record is available on https://clinicaltrials.gov/study/NCT05160818. The presented protocol refers to version V1.3 from March 21, 2021.

Single fraction stereotactic radiosurgery and fractionated stereotactic radiotherapy provide equal prognosis with overall survival in patients with brain metastases at diagnosis without surgery at primary site.

Stereotactic radiosurgery (SRS) and fractionated stereotactic radiation therapy (SRT) are both treatments shown to be effective in treating brain metastases (BMs). However, it is unknown how these treatments compare in effectiveness and safety in cancer patients with BMs regardless of the primary cancer. The main objective of this study is to investigate the SRS and SRT treatments' associations with the overall survival (OS) of patients diagnosed with BMs using the National Cancer Database (NCDB). Patients in the NCDB with breast cancer, non-small cell lung cancer, small cell lung cancer, other lung cancers, melanoma, colorectal cancer, or kidney cancer who had BMs at the time of their primary cancer diagnosis and received either SRS or SRT as treatment for their BMs were included in the study. We analyzed OS with a Cox proportional hazard analysis that adjusted variables associated with improved OS during univariable analysis. Of the total 6,961 patients that fit the criteria for the study, 5,423 (77.9%) received SRS and 1,538 (22.1%) received SRT. Patients who received SRS treatment had a median survival time of 10.9 (95% CI [10.5-11.3]), and those who received SRT treatment had a median survival time of 11.3 (95% CI [10.4-12.3]) months. This difference was not found to be significant (Log-rank P=0.31). Multivariable Cox proportional hazard analysis did not yield a significant difference between the treatments' associations with OS (Hazard Ratio: 0.942, CI 95% [0.882-1.006]; P=.08) or SRS vs. SRT. In this analysis, SRS and SRT did not show a significant difference in their associations with OS. Future studies investigating the neurotoxicity risks of SRS as compared to SRT are warranted.

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

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