Single-fraction Stereotactic Radiosurgery Research Articles

Stereotactic Radiosurgery for WHO Grade 2 and 3 Oligodendroglioma: An International Multicenter Study

INTRODUCTION: Oligodendrogliomas are primary brain tumors classified as IDH-mutant and 1p19q co-deleted in the 2021 WHO Classification. Surgery, fractionated radiotherapy and chemotherapy are well established treatments for these tumors, but there are few studies evaluating the efficacy of stereotactic radiosurgery (SRS). As these tumors are less infiltrative than astrocytomas and typically recur locally, they could be appropriate for local therapy such as SRS. METHODS: This was a retrospective multicenter study performed through the International Radiosurgery Research Foundation (IRRF). Adult patients were included if they underwent single-fraction SRS for a grade 2 or 3 oligodendroglioma. The primary endpoints were overall survival and progression-free survival. Secondary endpoints included clinical evolution and occurrence of adverse radiation events or other complications. RESULTS: Eight institutions submitted data for a total of 55 patients with a median clinical follow-up of 24 months. Median age at treatment was 46 years old and median pre-treatment KPS was 90. Median treatment volume was 4cc and median marginal dose delivered was 15Gy. The KPS remained stable post-SRS in 51% and worsened in 46.7% of patients, most often due to tumor progression (73.1%). Radiation-induced changes occurred in 29.6% of which 4 patients were symptomatic. Median progression-free survival was 17 months, with actuarial rates of 60.1% at 1 year, 31% at 2 years and 24.4% at 5 years after SRS. Median overall survival post-SRS was 58 months, with actuarial rates of 91.5% at 1 year, 83.4% at 2 years and 49.3% at 5 years post-SRS. Factors significantly associated with worsened survival were WHO grade 3 and prior radiotherapy and chemotherapy. Factors significantly associated with worsened PFS were WHO grade 3, prior radiotherapy and chemotherapy and higher treatment marginal dose. CONCLUSIONS: SRS appears to be a valuable management option for oligodendrogliomas.

Hypofractionated Stereotactic Radiosurgery in the Management of Brain Metastases.

Stereotactic radiosurgery (SRS) is an important weapon in the management of brain metastases. Single-fraction SRS is associated with local control rates ranging from approximately 70% to 100%, which are largely dependent on lesion and postoperative cavity size. The rates of local control and improved neurocognitive outcomes compared with conventional whole-brain radiation therapy have led to increased adoption of SRS in these settings. However, when treating larger targets and/or targets located in eloquent locations, the risk of normal tissue toxicity and adverse radiation effects within healthy brain tissue becomes significantly higher. Thus, hypofractionated SRS has become a widely adopted approach, which allows for the delivery of ablative doses of radiation while also minimizing the risk of toxicity. This approach has been studied in multiple retrospective reports in both the postoperative and intact settings. While there are no reported randomized data to date, there are trials underway evaluating this paradigm. In this article, we review the role of hypofractionated SRS in the management of brain metastases and emerging data that will serve to validate this treatment approach. Pertinent articles and references were obtained from a comprehensive search of PubMed/MEDLINE and clinicaltrials.gov .

Long-term radiographic and endocrinological outcomes of stereotactic radiosurgery for recurrent or residual nonfunctioning pituitary adenomas.

Stereotactic radiosurgery (SRS) is used for the treatment of residual/recurrent nonfunctional pituitary adenoma (NFPA). The aim of this study was to evaluate the factors related to long-term tumor control and delayed endocrinopathies following SRS. This retrospective, multicenter study included patients with recurrent/residual NFPA treated with single-fraction SRS; they were then divided into two arms. The first arm included patients with at least 5 years of radiographic follow-up and all patients with local tumor progression. The second arm included patients with at least 5 years of endocrinological follow-up and all patients who developed endocrinopathy. Study endpoints were tumor control and new or worsening hypopituitarism after SRS and were analyzed using Cox regression and Kaplan-Meier methodology. There were 360 patients in the tumor control arm (median age 52.7 [IQR 42.9-61] years, 193 [53.6%] males) and 351 patients in the hypopituitarism arm (median age 52.5 [IQR 43-61] years, 186 [53.0%] males). The median follow-up in the tumor control evaluation group was 7.95 (IQR 5.7-10.5) years. Tumor control rates at 5, 8, 10, and 15 years were 93% (95% CI 90%-95%), 87% (95% CI 83%-91%), 86% (95% CI 82%-90%), and 69% (95% CI 59%-81%), respectively. The median follow-up in the endocrinopathy evaluation group was 8 (IQR 5.9-10.7) years. Pituitary function preservation rates at 5, 8, 10, and 15 years were 83% (95% CI 80%-87%), 81% (95% CI 77%-85%), 78% (95% CI 74%-83%), and 71% (95% CI 63%-79%), respectively. A margin dose > 15 Gy (HR 0.8, 95% CI 0.7-0.9; p < 0.001) and a delay from last resection to SRS > 1 year (HR 0.9, 95% CI 0.7-0.9; p = 0.04) were significant factors related to tumor control in multivariable analysis. A maximum dose to the pituitary stalk ≤ 10 Gy (HR 1.1, 95% CI 1.09-1.2; p < 0.001) was associated with pituitary function preservation. New visual deficits after SRS occurred in 7 (1.94%) patients in the tumor control group and 8 (2.3%) patients in the endocrinopathy group. Other new cranial nerve deficits post-SRS occurred in 4 of 160 patients with data in the tumor control group and 3 of 140 patients with data in the endocrinopathy group. SRS affords favorable and durable tumor control for the vast majority of NFPAs. Post-SRS hypopituitarism occurs in a minority of patients, but this risk increases with time and warrants long-term follow-up.

31LBA (PB-012) LBA Poster - Pre-operative single-fraction stereotactic radiosurgery for early-stage breast cancer: pathological results

31LBA (PB-012) LBA Poster - Pre-operative single-fraction stereotactic radiosurgery for early-stage breast cancer: pathological results

Initial Experience With 6D Skull Tracking and Intrafractional Motion Monitoring in the United Arab Emirates' First CyberKnife® Radiosurgery Center.

Introduction The introduction of the CyberKnife® system has marked a significant advancement in the field of radiosurgery, offering unparalleled precision in targeting and treating cranial and extracranial lesions. This paper details the first experience from the United Arab Emirates in implementing 6D skull tracking and intrafractional motion monitoring in CyberKnife® radiosurgery. The study aims to evaluate the system's efficacy in tracking and adjusting patient movement during treatment, enhancing treatment accuracy and patient safety. Methods and materials This retrospective study analyzed 732 images from six patients treated at the UAE's first CyberKnife® center. Patients were divided into two groups based on their treatment regimens: Patients 1 to 4 (P1 to P4) received multifractionated stereotactic radiotherapy, while Patients 5 and 6 (P5 and P6) underwent single-fraction stereotactic radiosurgery (SRS). The movements recorded included supero-inferior, lateral, antero-posterior, roll, pitch, and yaw. Statistical tools were employed to interpret the data, including heat maps, box-and-whisker plots, and correlation analysis. Results The study's results indicate varied patterns of intrafractional movement across the different axes and between the two treatment groups. Multifractionated therapy patients exhibited a specific range and frequency of movements compared to those undergoing single-fraction treatment. The most significant movements were observed in the supero-inferior and lateral axes. Discussion The findings suggest that the CyberKnife® system's real-time tracking and adaptive capabilities are crucial in managing patient movements, especially in prolonged treatment sessions. The differences in movement patterns between multifractionated and single-fraction treatments underscore the need for tailored approaches in intrafractional motion monitoring. Conclusion The initial experience of the UAE's first CyberKnife® center demonstrates the system's effectiveness in addressing intrafractional movements, enhancing the precision and safety of radiosurgery treatments. This study contributes valuable insights into optimizing treatment protocols and underscores the importance of continuous monitoring and adaptive strategies in advanced radiosurgery.

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.

Single versus multiple fraction stereotactic radiosurgery for medium-sized brain metastases (4-14 cc in volume): reducing or fractionating the radiosurgery dose?

Stereotactic radiosurgery (SRS) of brain metastases (BM) and resection cavities is a widely used and effective treatment modality. Based on target lesion size and anatomical location, single fraction SRS (SF-SRS) or multiple fraction SRS (MF-SRS) are applied. Current clinical recommendations conditionally recommend either reduced dose SF-SRS or MF-SRS for medium-sized BM (2-2.9 cm in diameter). Despite excellent local control rates, SRS carries the risk of radionecrosis (RN). The purpose of this study was to assess the 12-months local control (LC) rate and 12-months RN rate of this specific patient population. This single-center retrospective study included 54 patients with medium-sized intact BM (n=28) or resection cavities (n=30) treated with either SF-SRS or MF-SRS. Follow-up MRI was used to determine LC and RN using a modification of the "Brain Tumor Reporting and Data System" (BT-RADS) scoring system. The 12-month LC rate following treatment of intact BM was 66.7% for SF-SRS and 60.0% for MF-SRS (p=1.000). For resection cavities, the 12-month LC rate was 92.9%% after SF-SRS and 46.2% after MF-SRS (p=0.013). For intact BM, RN rate was 17.6% for SF-SRS and 20.0% for MF-SRS (p=1.000). For resection cavities, RN rate was 28.6% for SF-SRS and 20.0% for MF-SRS (p=1.000). Patients with intact BM showed no statistically significant differences in 12-months LC and RN rate following SF-SRS or MF-SRS. In patients with resection cavities the 12-months LC rate was significantly better following SF-SRS, with no increase in the RNFS.

Treatment outcomes of single-fraction stereotactic radiosurgery for adenoid cystic carcinoma: a case series of 55 patients.

This study aimed to analyze the treatment outcomes of single-fraction stereotactic radiosurgery (SRS) for adenoid cystic carcinoma patients. Retrospective analysis was conducted for 55 patients with 66 lesions. SRS intentions were categorized as definitive, adjuvant, salvage, and palliative. Tumor control was defined as local (within 50% isodose line), marginal (outside 50% isodose line), and distant (metastasis outside head/neck). The median age was 60 years (range 21-85), with 53% males. Tumor origin was head/neck for 88% and trachea/lung for 12%. 61% were recurrent lesions. Median interval from diagnosis to SRS was 14 months. Preceding surgery was performed in 30%. SRS was administered as definitive (30 lesions), adjuvant (13), salvage (19), and palliative (4). SRS was used as a boost to external beam radiation therapy (EBRT) in 39%. Concurrent chemotherapy was administered in 26%. 5-, 10-, and 15-year local control rates were 60%, 33%, and 27%, respectively; local/marginal control rates were 29%, 13%, and 10%. For recurrent lesions treated with SRS without EBRT, 5-year local control rate was 14%, and local/marginal control rate was 5%. For recurrent lesions treated with SRS and EBRT, 5-year local control rate was 100%, and local/marginal control rate was 40%. The rate of distant failure after SRS was 40%. Older age and distant metastasis before SRS were negative factors for overall survival. SRS provided a high rate of local tumor control, but marginal failure was frequent. Integrating SRS with added EBRT exhibits potential for enhancing local and local/marginal tumor control, particularly in recurrent cases.

Effect of cerebral arteriovenous malformation location on outcomes of repeat, single-fraction stereotactic radiosurgery: a matched-cohort analysis.

Patients with deep-seated arteriovenous malformations (AVMs) have a higher rate of unfavorable outcome and lower rate of nidus obliteration after primary stereotactic radiosurgery (SRS). The aim of this study was to evaluate and quantify the effect of AVM location on repeat SRS outcomes. This retrospective, multicenter study involved 505 AVM patients managed with repeat, single-session SRS. The endpoints were nidus obliteration, hemorrhage in the latency period, radiation-induced changes (RICs), and favorable outcome. Patients were split on the basis of AVM location into the deep (brainstem, basal ganglia, thalamus, deep cerebellum, and corpus callosum) and superficial cohorts. The cohorts were matched 1:1 on the basis of the covariate balancing score for volume, eloquence of location, and prescription dose. After matching, 149 patients remained in each cohort. The 5-year cumulative probability rates for favorable outcome (probability difference -18%, 95% CI -30.9 to -5.8%, p = 0.004) and AVM obliteration (probability difference -18%, 95% CI -30.1% to -6.4%, p = 0.007) were significantly lower in the deep AVM cohort. No significant differences were observed in the 5-year cumulative probability rates for hemorrhage (probability difference 3%, 95% CI -2.4% to 8.5%, p = 0.28) or RICs (probability difference 1%, 95% CI -10.6% to 11.7%, p = 0.92). The median time to delayed cyst formation was longer with deep-seated AVMs (deep 62 months vs superficial 12 months, p = 0.047). AVMs located in deep regions had significantly lower favorable outcomes and obliteration rates compared with superficial lesions after repeat SRS. Although the rates of hemorrhage in the latency period and RICs in the two cohorts were comparable, delayed cyst formation occurred later in patients with deep-seated AVMs.

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.

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.

A Comparison of Local Failure and Necrosis Following Different Radiosurgery Strategies for Large Brain Metastases

Large brain metastases (LBMs) are associated with poor local control with single-fraction stereotactic radiosurgery (SRS) alone. Various alternative strategies have been developed, including fractionated SRS (FSRS) and staged SRS (SSRS) for intact LBMs, and resection with postoperative-SRS (postop-SRS) or preoperative-SRS (preop-SRS) for operable LBMs. The objective of this study is to compare local failure (LF) and radiation necrosis (RN) outcomes among these four management strategies to determine the optimal treatment paradigm. Consecutive patients diagnosed with LBM (≥2 cm in maximum dimension) between July 2017 and January 2022 and treated with one of the aforementioned strategies at a single tertiary institution were evaluated. All immobilization, target contouring, margins, dose- and prescription selection followed pre-defined institutional guidelines. Primary endpoints included LF, symptomatic RN, or a composite endpoint of these two variables. Gray's test was used to compare the cumulative incidence of the LF and the composite endpoint, with death as a competing risk. A total of 234 LBMs in 188 consecutive patients met the inclusion criteria. The median age was 65 years (range: 31-98), the median KPS was 80 (range: 50-100), and 58% were female. The most common primary tumors were lung (48%) and breast cancer (17%). The median maximum tumor diameter was 3.0 cm (range: 2.0-5.6). 47 (20%) lesions were treated with FSRS, 66 (28%) with SSRS, 74 (32%) with postop-SRS, and 47 (20%) with preop-SRS. With a median follow-up of 12 months, 22 (9%) LF and 11 (5%) RN events occurred. The 6-month and 1-year cumulative incidences of LF for the entire cohort were 5% (95% CI: 3%-9%) and 8% (95% CI: 5%-12%), respectively. The 6-month and 1-year LF rates were 4% (95% CI: 1%-13%) and 8% (95% CI: 3%-20%) for FSRS; 8% (95% CI: 3%-20%) and 8% (95% CI: 3%-20%) for SSRS; 7% (95% CI: 3%-15%) and 8% (95% CI: 3%-16%) for postop-SRS; 0 and 7% (95% CI: 2%-20%) for preop-SRS (p>0.05). The 1-year OS rates were favorable in resected patients (61% for postop-SRS and 82% for preop-SRS) compared to SRS alone strategies (45% for FSRS and 56% for SSRS) (p = 0.004). Similarly, RN events were significantly lower in resected patients treated with either bimodality approach (0 for postop-SRS and 4% for preop-SRS) than SRS standalone strategies (9% for FSRS and 8% SSRS) (p = 0.024). At 12 months, the cumulative probabilities of the composite endpoint were 13% (95% CI: 5%-25%) for FSRS, 15% (95% CI: 7%-25%) for SSRS, 9% (95% CI: 3%-17%) for postop-SRS, and 12% (95% CI: 4%-24%) for preop-SRS and not significantly different between the groups. For medically operable patients with surgically resectable LBMs, a strategy of surgery and SRS, regardless of timing, is associated with favorable local control and reduced risk for RN. For unresected patients, either SSRS or FSRS is associated with similar local control, but slightly higher RN risk. Prospective comparative evaluation is warranted.

Stereotactic Radiosurgery for Small Intact Brain Metastasis: A Comparative Evaluation of 3 Different Single Fraction Prescription Doses

While single-fraction stereotactic radiosurgery (SRS) in the treatment of small brain metastases (SBM, ≤ 2 cm) is well established, prescription dosing varies considerably across institutions and clinical trials. The choice of prescription dose is a delicate balance between local failure (LF) and radiation necrosis (RN) risks. In the modern era, historically-established dosing thresholds may no longer be applicable. To evaluate the impact of prescription dose on outcomes, we performed a comparative analysis of patients with SBM treated with definitive SRS using three different prescriptions, at a single tertiary institution. Consecutive patients with intact SBM treated with SRS from January 2017 and December 2021 were analyzed. Baseline patient characteristics and dosing parameters were abstracted from the medical record. To limit the integral brain dose when treating multiple brain metastases, the institutional practice was to reduce prescription dose as the total number of lesions increased (i.e., 24 Gy for ≤10 lesions, 22 Gy for 11-20, and 20 Gy for >20). A per lesion analysis, where each lesion was followed from the date of SRS to the last follow-up, was conducted with primary endpoints of LF and RN. Gray's test was used to compare the cumulative incidence of the LF and RN, with death as a competing risk. Factors affecting LF were analyzed using Cox hazard regression analysis. A total of 1318 SBM in 250 patients received SRS and met the inclusion criteria. The median age was 62 years (range: 18-90), median KPS was 90 (range: 50-100) and 66% were female. The most common primary tumors were lung (55.5%) and breast cancers (26.4%). With a median follow-up of 12 months, 136 (11%) LF in 44 patients and 70 (5.7%) RN events in 46 patients occurred. The actuarial 1-year cumulative rate of LF was lower in lesions treated with 24 Gy (6.4%, 95% CI: 4.7-8.6%) or 22 Gy (5.8%, 95% CI: 3.7-8.7%) compared to 20 Gy (15.4%, 95% CI: 10.9-20.5%) (p<0.01). 22 Gy and 24 Gy prescription doses were associated with a 44% and 52% reduction in risk in LF compared to 20 Gy (HR: 0.56; 95% CI: 0.36-0.9; p = 0.01 and HR: 0.48; 95% CI: 0.31-0.74; p<0.01, respectively). In a subset analysis of radiosensitive tumors, 1-year LF rate was still lower with 24 Gy (7.4%, 95% CI: 5.3-9.9%) and 22 Gy (6.1%, 95% CI: 3.7-9.4%) than 20 Gy (15.7%, 95% CI: 11.2-21%) (p = 0.01). The cumulative 1-year RN rate numerically declined with dose, but was not statistically significantly different, with 3.6% (95% CI: 2.3-5.3%) for 24 Gy, 2.6% (95% CI: 1.3-4.8%) for 22 Gy and 1.4% (95% CI: 0.4-3.7%) for 20 Gy. Patients treated with single fraction SRS to intact SBM were at increased risk of LF with prescription doses of 20 Gy compared to 22-24 Gy, without an increased risk of RN. Even in patients with radiosensitive histologies, higher LF rates were still observed following 20 Gy compared to 22-24 Gy.

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.

Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI): One-Year Safety and Efficacy Outcomes from a Multicenter Phase I Trial

The combination of immunotherapy and single-fraction stereotactic radiosurgery (SRS) for treatment of metastatic brain disease has yielded symptomatic radiation necrosis rates as high as 20% (PMID: 29327059). Consequently, the Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI) multicenter phase I trial (registered at clinicaltrials.gov, NCT04047602) was created to address whether reduced-dose SRS can improve morbidity without compromising efficacy. In this report we present our one-year findings. Eligibility for RADREMI enrollment required brain metastases patients with: a) Histologically-confirmed primary malignancy, b) Receipt of immunotherapy within 30 days of SRS, c) 1-10 MRI-visible brain metastases, d) Estimated median survival of at least 6 months (via disease-specific graded prognostic assessment), and e) No history of whole brain radiation therapy. Reduced-dose SRS utilized 18 Gy for lesions 0-2 cm, 14 Gy for lesions 2.1-3 cm, and 12 Gy for lesions 3.1-4 cm. Symptomatic radiation necrosis was defined as imaging findings consistent with radiation necrosis combined with clinical symptoms requiring steroid administration and/or operative intervention. Local control was defined by Response Assessment in Neuro-Oncology (RANO) criteria. From December 18, 2019 to June 30, 2022, 54 lesions in 17 patients were treated on RADREMI with at least one-year of follow-up. One-year local control occurred in 52 of 54 lesions and in 15 of 17 patients, yielding control rates of 96% per lesion and 88% per patient. Radiographic radiation necrosis occurred in 2 of 54 lesions (4%). No symptomatic radiation necrosis occurred. Our findings of concurrent immunotherapy + reduced-dose SRS at one-year post-treatment revealed excellent local control (96%) with no symptomatic radiation necrosis, and minimal radiographic radiation necrosis. These results attest to the durability of the safety and efficacy of reduced-dose SRS with immunotherapy for metastatic brain disease.

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.

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.