Stereotactic Radiosurgery For Brain Metastases Research Articles

Prediction of treatment response after stereotactic radiosurgery of brain metastasis using deep learning and radiomics on longitudinal MRI data

We developed artificial intelligence models to predict the brain metastasis (BM) treatment response after stereotactic radiosurgery (SRS) using longitudinal magnetic resonance imaging (MRI) data and evaluated prediction accuracy changes according to the number of sequential MRI scans. We included four sequential MRI scans for 194 patients with BM and 369 target lesions for the Developmental dataset. The data were randomly split (8:2 ratio) for training and testing. For external validation, 172 MRI scans from 43 patients with BM and 62 target lesions were additionally enrolled. The maximum axial diameter (Dmax), radiomics, and deep learning (DL) models were generated for comparison. We evaluated the simple convolutional neural network (CNN) model and a gated recurrent unit (Conv-GRU)-based CNN model in the DL arm. The Conv-GRU model performed superior to the simple CNN models. For both datasets, the area under the curve (AUC) was significantly higher for the two-dimensional (2D) Conv-GRU model than for the 3D Conv-GRU, Dmax, and radiomics models. The accuracy of the 2D Conv-GRU model increased with the number of follow-up studies. In conclusion, using longitudinal MRI data, the 2D Conv-GRU model outperformed all other models in predicting the treatment response after SRS of BM.

Lexicographic optimization-based planning for stereotactic radiosurgery of brain metastases

AimTo validate a fully-automated lexicographic optimization-planning system (mCycle, Elekta) for single-(SL) and multiple-(ML, up to 4 metastases) lesions in intracranial stereotactic radiosurgery (SRS, 21 Gy, single fraction). MethodsA pre-determined priority list, Wish-List (WL), represents a dialogue between planner and clinician, establishing strict constraints and pursuing objectives. In order to satisfy the clinical protocol without manual intervention, four patients were required to tweak and fine-tune each WL (SLp, MLp) for coplanar arcs. Thirty-five testing plans (20 SLp, 15 MLp) were automatically re-planned (mCP). Automatic and manual plans were compared including dose constraints, conformality, modulation complexity score (MCS), delivery time, and local gamma analysis (2%/2 mm). To ensure plan clinical acceptability, two radiation oncologists conducted an independent blind plan choice. ResultsEach WL-tuning took 3 days. Estimated median manual plans and mCP calculation time were 8 and 3 h, respectively. Significant increases in SLp and MLp target coverage and conformity were registered. mCP showed a not significant and clinically acceptable higher median brain V12Gy. SLp registered a −5.8% MU decrease with comparable median delivery time (MP 2.0 min, mCP 1.9 min) while MLp showed a +9.8% MU increase and longer delivery time (MP 3.5 min, mCP 4.4 min). mCP MCS resulted significantly higher without affecting gamma passing rates. At blind choice, mCP were preferred in the majority of cases. ConclusionsLexicographic optimization produced acceptable SRS plans with coplanar arcs significantly reducing the overall planning time in cases with up to 4 brain metastases. These planning improvements suggest further investigations by setting high-quality non-coplanar arc plans as a reference.

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

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

Dose-Incorporated Deep Ensemble Learning for Improving Brain Metastasis Stereotactic Radiosurgery Outcome Prediction

Purpose/Objective(s)To develop a novel deep ensemble learning model for accurate prediction of brain metastasis(BM) local control outcomes following stereotactic radiosurgery(SRS). Materials/MethodsA total of 114 BMs from 82 patients were evaluated, including 26 BMs that developed biopsy-confirmed local failure post-SRS. The SRS spatial dose distribution(Dmap) of each BM was registered to the planning contrast-enhanced T1(T1-CE) MR. Axial slices of the Dmap, T1-CE, and PTV segmentation(PTVseg) intersecting the BM center were extracted within a fixed field-of-view determined by the V60% in Dmap. A spherical projection was implemented to transform planar image content onto a spherical surface using multiple projection centers, and the resultant T1-CE/Dmap/PTVseg projections were stacked as a 3-channel variable. Four VGG-19 deep encoders were utilized in an ensemble design, with each sub-model using a different spherical projection formula as input for BM outcome prediction. In each sub-model, clinical features after positional encoding were fused with VGG-19 deep features to generate logit results. The ensemble's outcome was synthesized from the four sub-model results via logistic regression. A total of 10 model versions with random validation sample assignments were trained to study model robustness. Performance was compared to 1) a single VGG-19 encoder; 2) an ensemble with T1-CE MRI as the sole image input after projections; and 3) an ensemble with the same image input design without clinical feature inclusion. ResultsThe ensemble model achieved an excellent AUCROC=0.89±0.02 with high sensitivity(0.82±0.05), specificity(0.84±0.11), and accuracy(0.84±0.08) results. This outperformed the MRI-only VGG-19 encoder (sensitivity:0.35±0.01, AUC:0.64±0.08), the MRI-only deep ensemble (sensitivity:0.60±0.09, AUC:0.68±0.06), and the 3-channel ensemble without clinical feature fusion (sensitivity:0.78±0.08, AUC:0.84±0.03). ConclusionFacilitated by the spherical image projection method, a deep ensemble model incorporating Dmap and clinical variables demonstrated an excellent performance in predicting BM post-SRS local failure. Our novel approach could improve other radiotherapy outcome models and warrants further evaluation.

Impact of Planning Target Volume Margins in Stereotactic Radiosurgery for Brain Metastasis: A Review

Impact of Planning Target Volume Margins in Stereotactic Radiosurgery for Brain Metastasis: A Review

Prognosis versus Actual Outcomes in Stereotactic Radiosurgery of Brain Metastases: Reliability of Common Prognostic Parameters and Indices.

This study aims to evaluate the clinical outcome of stereotactic radiosurgery as the sole treatment for brain metastases and to assess prognostic factors influencing survival. A total of 108 consecutive patients with 213 metastases were retrospectively analyzed. Treatment was determined with close-meshed MRI follow-up. Various prognostic factors were assessed, and several prognostic indices were compared regarding their reliability to estimate overall survival. Median overall survival was 15 months; one-year overall survival was 50.5%. Both one- and two-year local controls were 90.9%. The rate of new metastases after SRS was 49.1%. Multivariate analysis of prognostic factors revealed that the presence of extracranial metastases, male sex, lower KPI, and progressive extracranial disease were significant risk factors for decreased survival. Of all evaluated prognostic indices, the Basic Score for Brain Metastases (BSBMs) showed the best correlation with overall survival. A substantial survival advantage was found for female patients after SRS when compared to male patients (18 versus 9 months, p = 0.003). SRS of brain metastasis is a safe and effective treatment option when frequent monitoring for new metastases with MRI is performed. Common prognostic scores lack reliable estimation of survival times. Female sex should be considered as an additional independent positive prognostic factor influencing survival.

Surgery of enlarging lesions after stereotactic radiosurgery for brain metastases in patients with non-small cell lung cancer with oncogenic driver mutations frequently reveals radiation necrosis: case series and review.

In brain metastases, radiation necrosis (RN) is a complication that arises after single or multiple fractionated stereotactic radiosurgery (SRS/FSRS), which is challenging to distinguish from local recurrence (LR). Studies have shown increased RN incidence rates in non-small cell lung cancer (NSCLC) patients with oncogenic driver mutations (ODMs) or receiving tyrosine kinase inhibitors (TKIs). This study investigated enlarging brain lesions following SRS/FSRS, for which additional surgeries were performed to distinguish between RN and LR. We investigated seven NSCLC patients with ODMs undergoing SRS/FSRS for BM and undergoing surgery for suspicion of LR on MRI imaging. Descriptive statistics were performed. Among the seven patients, six were EGFR+, while one was ALK+. The median irradiation dose was 30 Gy (range, 20-35 Gy). The median time to develop RN after SRS/FSRS was 11.1 months (range: 6.3-31.2 months). Moreover, gradually enlarging lesions were found in all patients after 6 months post-SRS/FSR. Brain radiation necrosis was pathologically confirmed in all the patients. RN should be suspected in NSCLC patients when lesions keep enlarging after 6 months post-SRS/FSRS, especially for patients with ODMs and receiving TKIs. Further, this case series indicates that further dose reduction might be necessary to avoid RN for such patients.

Stereotactic radiosurgery for brain metastases arising from gynecological malignancies: A retrospective treatment outcome analysis

BackgroundThis retrospective study aims to assess the efficacy of stereotactic radiosurgery (SRS) in the treatment of brain metastases (BM) originating from gynecological cancers. It focuses on local control (LC), distant tumor control (DTC), and overall survival (OS). MethodsThe analysis comprised 18 individuals with gynecological-origin BM treated with SRS at the Hadassah Medical Center from 2004 to 2021. Statistical analyses evaluate factors impacting LC, DTC, and OS. ResultsA total of 36 BM of gynecological origin underwent SRS. The median age at the first SRS treatment was 60 years, with a median time of 24.5 months from the primary malignancy diagnosis to BM detection. The 12-month LC rate per patient was 84.6 %, and 5.6 % per BM. Only two instances of local recurrence were observed. The DTC at 12 months was 75 %, with a 29 % overall. Non-significant trends indicating a correlation with distant brain failure with increased cumulative volume and the occurrence of craniotomy before SRS. The median OS of the cohort was 16.5 months from SRS treatment. The 6, 12, 18, and 24-month survival rates were 77.8 %, 66.7 %, 50 %, and 22.2 % respectively. Higher number of BM was associated with lower OS (p = 0.046). On multivariate analysis, age was a significant factor for OS (p = 0.03), demonstrating that older age was associated with a more favorable prognosis. ConclusionThis study supports SRS effectiveness for treating BM from gynecological cancers and suggests similar outcomes to more common malignancies.

Adverse radiation effect versus tumor progression following stereotactic radiosurgery for brain metastases: Implications of radiologic uncertainty.

Adverse radiation effect (ARE) following stereotactic radiosurgery (SRS) for brain metastases is challenging to distinguish from tumor progression. This study characterizes the clinical implications of radiologic uncertainty (RU). Cases reviewed retrospectively at a single-institutional, multi-disciplinary SRS Tumor Board between 2015-2022 for RU following SRS were identified. Treatment history, diagnostic or therapeutic interventions performed upon RU resolution, and development of neurologic deficits surrounding intervention were obtained from the medical record. Differences in lesion volume and maximum diameter at RU onset versus resolution were compared with paired t-tests. Median time from RU onset to resolution was estimated using the Kaplan-Meier method. Univariate and multivariate associations between clinical characteristics and time to RU resolution were assessed with Cox proportional-hazards regression. Among 128 lesions with RU, 23.5% had undergone ≥ 2 courses of radiation. Median maximum diameter (20 vs. 16mm, p < 0.001) and volume (2.7 vs. 1.5cc, p < 0.001) were larger upon RU resolution versus onset. RU resolution took > 6 and > 12months in 25% and 7% of cases, respectively. Higher total EQD2 prior to RU onset (HR = 0.45, p = 0.03) and use of MR perfusion (HR = 0.56, p = 0.001) correlated with shorter time to resolution; larger volume (HR = 1.05, p = 0.006) portended longer time to resolution. Most lesions (57%) were diagnosed as ARE. Most patients (58%) underwent an intervention upon RU resolution; of these, 38% developed a neurologic deficit surrounding intervention. RU resolution took > 6months in > 25% of cases. RU may lead to suboptimal outcomes and symptom burden. Improved characterization of post-SRS RU is needed.

Complete pathological response after primary tumor surgery following chemoimmunotherapy and stereotactic radiosurgery of initially metastatic non-small-cell lung cancer

Introduction Surgery of the primary tumor following extended course of chemoimmunotherapy has only recently been recognized as a feasible and safe option for selected groups of patients with initially unresectable non-small cell lung cancer. Case outline Here we report a case of a 49-year-old never smoking female patient that was diagnosed with metastatic non-small cell lung cancer. Lesions were evident in both lungs and the brain. She underwent stereotactic radiosurgery for brain metastases and combination therapy of chemotherapy, atezolizumab and bevacizumab. Response to therapy was both remarkable and durable. Ten cycles into treatment MRI of the brain revealed no metastatic lesions. PET/CT revealed a single lesion in the right upper lobe 22x23mm in diameter. The patient underwent a right upper lobectomy. Patohistological evaluation of the specimen revealed complete pathologic response. The patient recovered from surgery and continued chemoimmunotherapy. For four months post-surgery she is disease free and of excellent performance status. Conclusion Primary tumor surgery following extensive chemoimmunotherapy regiment is feasible and could be considered as a treatment option. Further research is warranted to define a patient population that stands to benefit the most from this modality.

Stereotactic radiosurgery of brain metastases: a retrospective study

BackgroundSingle-fraction stereotactic radiosurgery (SRS) is an established standard for radiation therapy of brain metastases although recent developments indicate that multi-fractionated stereotactic radiotherapy (FSRT) results in lower radiation necrosis especially for larger metastases, and the same or even better local control in comparison to SRS.MethodsSeventy-two patients with 111 brain metastases received SRS with a single dose of 18 Gy between September 2014 and December 2021. The dose prescription was either 18 Gy given to the enclosing 80% isodose with a normalization to Dmax = 100% of 22.5 Gy (part I) or 18 Gy = D98, while D0.03 cc of 21.6–22.5 Gy was accepted (part II). The study retrospectively evaluated local progression-free survival (LPFS), response on the first follow-up magnetic resonance imaging (MRI), and radiation necrosis.ResultsMelanoma brain metastases (n = 44) were the most frequent metastases. The median gross tumor volume (GTV) was 0.30 cm³ (IQR, 0.17–0.61). The median follow-up time of all patients was 50.8 months (IQR, 30.4–64.6). Median LPFS was 23.5 months (95%CI 17.2, 29.8). The overall LPFS rates at 12-, 18-, 24- and 30 months were 65.3%, 56.3%, 46.5%, and 38.8%. Brain metastases with radioresistant histology (melanoma, renal cell cancer, and sarcoma) showed a 12-month LPFS of 60.2%, whereas brain metastases with other histology had a 12-month LPFS of 70.1%. The response of brain metastases on first follow-up MRIs performed after a median time of 47 days (IQR, 40–63) was crucial for long-term local control and survival. Eight brain metastases (7.2%) developed radiation necrosis after a median time of 18.4 months (IQR, 9.4–26.5). In multivariate analyses, a GTV > 0.3 cm³ negatively affected LPFS (HR 2.229, 95%CI 1.172, 4.239). Melanoma, renal cell cancers, and sarcoma had a lower chance of LPFS in comparison to other cancer types (HR 2.330, 95%CI 1.155, 4.699).ConclusionsOur results indicate a reasonable 1-year local control of brain metastases with radiosensitive histology. Radioresistant metastases show a comparatively poor local control. Treatment refinements merit exploration to improve local control of brain metastases.Trial registrationThis study is retrospectively registered (ethics approval number 23-3451-104).

10162-STMO-8 A SINGLE CENTER RETROSPECTIVE ANALYSIS OF AWAKE CRANIOTOMY FOR BRAIN METASTASIS.

Abstract BACKGROUND/AIM Awake surgery is often used for resecting glioma, but it is controversial whether it should be performed for brain metastasis, because brain tumor is rather demarcated than glioma. However, a small number of hospitals can perform awake craniotomy by limitation of hospital capacity. Here we show a single center retrospective analysis of awake craniotomy for brain metastasis to examine the safety and efficacy of awake craniotomy. MATERIAL/METHOD We analyzed consecutive 50 cases from January 2016 to May 2023 in our hospital. Rehabilitation staff evaluated their neurological status within a week before and after surgery. RESULT Patients characteristics were as follow. Median age was 62 (16-81). Left side tumor were 43 (86.0%). Frontal lobe was 36 (72.0%),temporal lobe 8 (16.0%), parietal lobe 5 (10.0%), occipital lobe 1 (2.0%). Primary cancer was lung 26 (52.0%), gastrointestinal lesion 7 (14.0%), breast 6 (12.0%), soft tissues 4 (8.0%), uterus 1 and malignant melanoma 1, respectively. Radiation necrosis after stereotactic radiosurgery for brain metastases was 5 (10.0%). Preoperative KPS 100-90 was 25 (50.0%), KPS 80 was 10 (20.0%) and less than or equal to KPS 70 was 15 (30.0%). Gross total removal was 43, partial removal was 7. MMSE of before and after surgery was mean 27.1 and median 29. Median OS was 18.8 months (95%CI: 11.2-526). DISCUSSION/CONCLUSION We selected most awake craniotomy for a tumor on left frontal lobe and each evaluationg scales showed no deterioration. Awake craniotomy for brain metastasis is probed to be performed without deteriorating patient's neurological function.

NCMP-04. INITIAL REPORT OF BOSWELLIA SERRATA FOR MANAGEMENT OF CEREBRAL RADIATION NECROSIS AFTER STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES

Abstract BACKGROUND Radiation necrosis(RN) is a concerning late toxicity after radiation therapy(RT) for brain metastases(BM). Oral corticosteroids are the mainstay of management; however, not optimal given multiple side effects, particularly with the emergence of immunotherapy. Boswellia serrata(BS) is an over-the-counter supplement shown to reduce cerebral edema after brain RT. We evaluated the response rates with BS in a series of BM patients treated with stereotactic radiosurgery(SRS) who developed RN. METHODS We enrolled patients who developed RN after SRS for BM from 2020-2022 and were treated with BS 4.2-4.5g daily. Response was assessed using Response Assessment in Neuro-Oncology(RANO) criteria. Primary endpoint was ≥25% decrease in edema volume on T2-FLAIR MRI from baseline. RESULTS Fifty patients received BS for Grade 1-3 CTCAE v5.0 RN (G1=11, G2=36, and G3=3). Median time to RN was 10 months(m) after SRS and median follow-up was 6m. Best response was a complete response(CR) in 15% patients and partial response(PR) in 40% while 35% had stable disease(SD) and 10% had progression. At 3 , 6 , 9 and 12 months of follow-up respectively, 25%, 60%, 43% and 50% patients had any response(CR or PR). About 56% patients had symptomatic RN, of which 35.7% had improvement in symptoms with BS alone, while 64% required steroid use. Overall, median duration of response in patients with CR, PR or SD was 7.5m(range 2-31m). Salvage treatment for RN was steroids(33), surgery(4), Bevacizumab(5) or hyperbaric oxygen(1). No patient had ≥ CTCAE grade 3 toxicities, while 6% had grade 1-2 gastrointestinal intolerance. Overall, 39 patients remained on BS at last follow-up or death. CONCLUSION We observed &amp;gt; 50% response rates with use of BS in patients with grade 1-3 RN after SRS. Over 1/3rd patients with symptomatic RN were able to avoid long-term steroid use. Further prospective studies comparing Boswellia with placebo are warranted.

RADT-18. PROTON CRANIOSPINAL IRRADIATION WITH CHECKPOINT INHIBITOR THERAPY FOR PATIENTS WITH LEPTOMENINGEAL DISEASE FROM SOLID TUMORS – A SINGLE INSTITUTION CASE SERIES

Abstract BACKGROUND Leptomeningeal disease (LMD) is a devastating complication of cancer with median overall survival (OS) of 3-6 months following diagnosis. Proton craniospinal irradiation (pCSI) is a novel treatment option for LMD, permitting whole neuroaxis treatment with tolerable toxicity and improved efficacy compared to conventional photon whole brain radiation therapy and as needed focal spine radiotherapy. Despite this, patients experience progression and succumb to LMD. Addition of systemic therapy to pCSI may improve outcomes. METHODS In this single institution retrospective case series, we report feasibility of combination treatment with pCSI and immune checkpoint inhibitor (ICI) in patients with LMD from solid tumors. RESULTS Three patients were treated with pCSI (30 Gy in 10 fractions) and ICI. The first patient developed LMD related to large cell neuroendocrine carcinoma of lung primary, diagnosed by imaging and cytology, having previously undergone resection and stereotactic radiosurgery for brain metastases. Clinical and radiographic improvement was noted following pCSI, bevacizumab, and pembrolizumab therapy. Patient experienced disease progression and passed away only after ICI was held due to hypophysitis, with 6-month OS. The second patient developed LMD related to BRAF V600E mutant melanoma, diagnosed by imaging and cytology, having previously undergone ICI and BRAF-targeted therapy. Following pCSI, relatlimab, nivolumab, and BRAF-targeted therapy, the patient remains alive 7 months after LMD diagnosis despite radiographic progression treated with carboplatin, paclitaxel, intrathecal IL-2, ipilimumab, and bevacizumab. The third developed LMD related to BRAF-wildtype melanoma, diagnosed by imaging, having previously received ICI. Patient underwent pCSI followed by ipilimumab and nivolumab, progression-free 5 months after LMD diagnosis. CONCLUSION Addition of systemic therapy to pCSI is feasible for patients with LMD. Combination of ICI and pCSI may confer additional survival benefit, even among patients with prior exposure to ICI. These initial promising results warrant prospective evaluation.

Response Assessment in Brain Metastases Managed by Stereotactic Radiosurgery: A Reappraisal of the RANO-BM Criteria.

Brain metastases (BM) are increasingly being treated using stereotactic radiosurgery (SRS). Standardized response criteria are necessary to improve research and treatment protocols. This study's goal was to validate the RANO-BM criteria thresholds for tumor progression in a cohort of patients with brain metastases managed using SRS. We performed a retrospective analysis of patients treated at least twice with SRS for brain metastases. Local progression, as defined by RANO-BM criteria, was compared to our multidisciplinary tumor board's treatment recommendation. A ROC curve was generated using varying diameter thresholds to assess the sensitivity and specificity of current RANO-BM criteria. 249 metastases in 67 patients were included in the analysis. RANO-BM criteria current progression thresholds yielded a sensitivity of 38%, a specificity of 95%, a positive predictive value of 71%, and a negative predictive value of 84% relative to our tumor board's treatment recommendation. Modified RANO-BM criteria using absolute diameter differences of 2.5 mm yielded a sensitivity of 83%, a specificity of 87%, a positive predictive value of 67% and a negative predictive value of 94%. Current RANO-BM criteria unreliably identifies clinically relevant tumor progression. The use of absolute diameter differences thresholds appears superior in our BM cohort.

Delayed Imaging Changes 18 Months or Longer After Stereotactic Radiosurgery for Brain Metastases: Necrosis or Progression

Imaging changes after stereotactic radiosurgery (SRS) can occur for years after treatment, although the available data on the incidence of tumor progression and adverse radiation effects (ARE) are generally limited to the first 2 years after treatment. A single-institution retrospective review was conducted of patients who had >18 months of imaging follow-up available. Patients who had ≥1 metastatic brain lesions treated with Gamma Knife SRS were assessed for the time to radiographic progression. Those with progression ≥18 months after the initial treatment were included in the present study. The lesions that progressed were characterized as either ARE or tumor progression based on the tissue diagnosis or imaging characteristics over time. The cumulative incidence of delayed imaging radiographic progression was 35% at 5 years after the initial SRS. The cumulative incidence curves of the time to radiographic progression for lesions determined to be ARE and lesions determined to be tumor progression were not significantly different statistically. The cumulative incidence of delayed ARE and delayed tumor progression was 17% and 16% at 5 years, respectively. Multivariate analysis indicated that the number of metastatic brain lesions present at the initial SRS was the only factor associated with late radiographic progression. The timing of late radiographic progression does not differ between ARE and tumor progression. The number of metastatic brain lesions at the initial SRS is a risk factor for late radiographic progression.

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.

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.

Clinical Outcomes for Patients with Brain Metastases from Upper Gastrointestinal Cancer Treated with Stereotactic Radiosurgery

Prior studies have reported outcomes for brain metastases from gastrointestinal (GI) primary cancers treated with stereotactic radiosurgery (SRS); however, most include a majority of colorectal cancer. Few studies specifically evaluate SRS treatment response for brain metastases from upper GI cancers. We report our institutional outcomes for patients with upper GI cancers who were treated with SRS for brain metastases. Patients with an upper GI cancer who underwent SRS for brain metastases between 1991 and 2021 were retrospectively reviewed from a single institution IRB-approved database. The primary endpoint was local failure (LF) and secondary endpoint was overall survival (OS). LF was estimated using the Cumulative Incidence Function with death as a competing risk. Survival analysis was performed with the Kaplan-Meier Method. Predictors of cumulative incidence of LF were assessed using competing risk regression. Forty-nine patients with 107 brain metastases were analyzed. Forty-two (86%) patients were male. The median follow-up time was 6.7 months (range: 0.4-61.7 months) and median OS was 7.5 months (range: 0.9-61.7 months). The median Karnofsky Performance Score (KPS) was 80 (range: 40-100). The primary disease site was esophagus in 87 (81%) lesions, pancreas in 10 (9.3%) lesions, stomach in 5 (4.7%) lesions, liver in 2 (1.9%) lesions, gallbladder in 2 (1.9%) lesions, and small intestine in 1 (0.9%) lesion. The median metastasis size was 1.4 cm (range: 0.3-6.7 cm). The median prescription dose and fraction number were 24 Gy (range: 14-30 Gy) and 1 fraction (range: 1-2 fractions), respectively. The cumulative incidence of LF at 6 and 12 months was 5.6% (95% CI: 2.3-11%) and 12% (95% CI: 6.9-20%), respectively. Overall survival at 6 and 12 months was 59% (95% CI: 50-69%) and 35% (95% CI: 27-46%), respectively. On univariate analysis, female gender (HR = 0.19, 95% CI: 0.06-0.61, p = 0.005), Black race (HR = 0.09, 95% CI: 0.03-0.23, p = <0.001), and larger tumors (HR = 1.35, 95% CI: 1.03-1.78, p = 0.03) were significantly associated with local failure. SRS for brain metastases from upper GI cancers is an appropriate treatment option and provides excellent local control. Unlike prior studies that have reported lower local control rates for all GI cancers with brain metastases treated with SRS, our data show that local failure rates in brain metastases from upper GI cancers specifically are more consistent with previously published data from other disease sites. Further studies evaluating SRS treatment response for brain metastases from GI cancers should separate upper GI and lower GI cancers.

Initial Report of Boswellia Serrata for Management of Cerebral Radiation Necrosis after Stereotactic Radiosurgery for Brain Metastases

Radiation necrosis (RN) is a concerning late toxicity after radiation therapy (RT) for brain metastases. Oral corticosteroids are the mainstay of management; however, they are not optimal for long-term use given multiple side effects and drug interactions, particularly with the emergence of immunotherapy for several cancers. Boswellia serrata (BS) is an over-the-counter supplement used for its anti-inflammatory properties and has been recently shown to reduce cerebral edema after brain RT. We evaluated the response rates with BS in a series of patients with brain metastases treated with stereotactic radiosurgery (SRS) who developed RN. We included patients who developed RN after SRS for brain metastases at our institution from 2020-2022 and were treated with BS. Patients were prescribed over the counter BS 4.2-4.5g daily in divided doses. Follow-up MRI imaging was obtained every 2-3 months after starting BS. Response was assessed using Response Assessment in Neuro-Oncology (RANO) criteria. Primary endpoint was ≥25% decrease in edema volume on T2-FLAIR MRI from baseline. Patients were censored if they had tumor progression or repeat RT to necrotic area, or death. Kaplan-Meier curves were used for survival estimates. A total of 50 patients received BS for Grade 1-3 CTCAE v5.0 RN (G1 = 11, G2 = 36, and G3 = 3). Median age was 62.8 years (range 36.9 - 50) and median RT dose was 24 Gy in 3 fractions. Median time to RN after SRS was 10 months(m). Median follow-up after starting BS was 6m and 40 patients had at least 1 follow up MRI available to evaluate response. The best response was complete response (CR) in 15% patients and partial response (PR) in 40% while 35% had stable disease (SD) and 10% had progressive disease. Median time to CR was 9m (6-12m) and PR was 6m (3-12m). Percentage of patients who had any response (CR or PR) at 3, 6, 9 and 12 months was 25%, 60%, 43% and 50%, respectively. 56% patients had symptomatic RN, of which 35.7% had improvement in symptoms with BS alone, while 64% required steroid use. Overall, median duration of response in patients with CR, PR or SD was 7.5m(range 2-31m). Salvage treatment for RN was steroids (33), surgery (4), Bevacizumab (5) or hyperbaric oxygen therapy (1). No patients had any CTCAE grade 3 or higher toxicities. 3 patients (6%) had any side-effects all of whom had Grade 1-2 gastrointestinal intolerance or diarrhea. 2 patients stopped treatment due to enrolment on an immunotherapy clinical trial. Overall, 39 patients remained on BS at last follow-up or death. We observed >50% response rates with use of BS in our cohort of patients with Grade 1-3 RN after SRS. More than 1/3rd patients with symptomatic RN were able to avoid long-term steroid use. BS is an easily available over-the-counter drug that appears to be a safe and promising treatment option for RN, and can potentially decrease steroid dependence in these patients, reducing the risk of several side-effects. Further prospective studies to compare Boswellia with placebo is warranted.