Beyond the surface: how ex-vivo diffusion-weighted imaging reveals large animal brain microstructure and connectivity.

Diffusion-weighted Imaging (DWI) is an effective and state-of-the-art neuroimaging method that non-invasively reveals the microstructure and connectivity of tissues. Recently, novel applications of the DWI technique in studying large brains through ex-vivo imaging enabled researchers to gain insights into the complex neural architecture in different species such as those of Perissodactyla (e.g., horses and rhinos), Artiodactyla (e.g., bovids, swines, and cetaceans), and Carnivora (e.g., felids, canids, and pinnipeds). Classical in-vivo tract-tracing methods are usually considered unsuitable for ethical and practical reasons, in large animals or protected species. Ex-vivo DWI-based tractography offers the chance to examine the microstructure and connectivity of formalin-fixed tissues with scan times and precision that is not feasible in-vivo. This paper explores DWI's application to ex-vivo brains of large animals, highlighting the unique insights it offers into the structure of sometimes phylogenetically different neural networks, the connectivity of white matter tracts, and comparative evolutionary adaptations. Here, we also summarize the challenges, concerns, and perspectives of ex-vivo DWI that will shape the future of the field in large brains.

Comparative evaluation of outcomes amongst different radiosurgery management paradigms for patients with large brain metastasis.

INTRODUCTION: This study compares four management paradigms for large brain metastasis (LMB): fractionated SRS (FSRS), staged SRS (SSRS), resection and postoperative-FSRS (postop-FSRS) or preoperative-SRS (preop-SRS). METHODS: Patients with LBM (≥ 2 cm) between July 2017 and January 2022 at a single tertiary institution were evaluated. Primary endpoints were local failure (LF), radiation necrosis (RN), leptomeningeal disease (LMD), a composite of these variables, and distant intracranial failure (DIF). Gray's test compared cumulative incidence, treating death as a competing risk with a random survival forests (RSF) machine-learning model also used to evaluate the data. RESULTS: 183 patients were treated to 234 LBMs: 31.6% for postop-FSRS, 28.2% for SSRS, 20.1% for FSRS, and 20.1% for preop-SRS. The overall 1-year composite endpoint rates were comparable (21 vs 20%) between nonoperative and operative strategies, but 1-year RN rate was 8 vs 4% (p = 0.012), 1-year overall survival (OS) was 48 vs. 69% (p = 0.001), and 1-year LMD rate was 5 vs 10% (p = 0.052). There were differences in the 1-year RN rates (7% FSRS, 3% postop-FSRS, 5% preop-SRS, 10% SSRS, p = 0.037). With RSF analysis, the out-of-bag error rate for the composite endpoint was 47%, with identified top-risk factors including widespread extracranial disease, > 5 total lesions, and breast cancer histology. CONCLUSION: This is the first study to conduct a head-to-head retrospective comparison of four SRS methods, addressing the lack of randomized data in LBM literature amongst treatment paradigms. Despite patient characteristic trends, no significant differences were found in LF, composite endpoint, and DIF rates between non-operative and operative approaches.

Constrained spherical deconvolution on diffusion-weighted images of dolphin brains.

Invasive neuronal tract-tracing is not permitted in very large or endangered animals. This is especially the case in marine mammals like dolphins. Diffusion-weighted imaging of fiber tracts could be an alternative if feasible even in brains that have been fixed in formalin for a long time. This currently is a problem, especially for detecting crossing fibers. We applied a state-of-the-art algorithm of Diffusion-weighted imaging called Constrained Spherical Deconvolution on diffusion data of three fixed brains of bottlenose dolphins using clinical human MRI parameters and were able to identify complex fiber patterns within a voxel. Our findings indicate that in order to maintain the structural integrity of the tissue, short-term post-mortem fixation is necessary. Furthermore, pre-processing steps are essential to remove the classical Diffusion-weighted imaging artifacts from images: however, the algorithm is still able to resolve fiber tracking in regions with various signal intensities. The described imaging technique reveals complex fiber patterns in cetacean brains that have been preserved in formalin for extended periods of time and thus opens a new window into our understanding of cetacean neuroanatomy.

Multi-institutional study of 'Sandwich treatment' for motor area large brain metastases (LBM) with diameter over 3 cm.

BACKGROUND: The objective of the present study was to explore the effectiveness and safety of 'Sandwich treatment' strategy for large brain metastases (LBM) with diameter over 3 cm (minimum volume >= 15 cm3) located in motor area. PATIENTS AND METHODS: Patients from four gamma knife center that received 'Sandwich treatment' were retrospectively studied from January 2016 to March 2023. The strategy was one-week treatment course including 2 stages of stereotactic radiosurgery (SRS) and using bevacizumab once during SRS gap. The tumor volume and peri-tumor edema changes were analyzed before and after 'Sandwich treatment'. Manual muscle testing (MMT) score and Barthel Index (BI) score were used to evaluate the changes of patients' movement and physical strength rehabilitation. The patients' overall survival (OS) and tumor local control (TLC) rate was calculated. Cox regression model was used to analyze the risk factors that related to TLC. RESULTS: 61 patients with 72 lesions received the 'Sandwich treatment'. The median prescription dose was 13.0 Gy and 12.5 Gy at the first- and second-stage SRS. The mean tumor volume at the time of 'Sandwich treatment' and 3 months later was 20.1 cm3 and 12.3, respectively (P < 0.01). The mean peri-tumor edema volume at the first- and second-stage SRS was 12.6 cm3 and 5.2 cm3, respectively (P < 0.01). Patients' median MMT score improved from 6 at the beginning to 8 at the end of 'Sandwich treatment' (P < 0.01), BI score was also greatly improved from 45 at the time of 'Sandwich treatment' to 95 after 3 months (P < 0.01). Patients' median OS was 14.0 months, and the 3, 6, 12 months OS rate was 92.0%, 86.0% and 66.0%, respectively. The TLC rate at 3, 6, 12 months was 98.4%, 93.4%, and 85.3%, respectively. Patients with lung cancer had lower risk of tumor relapse. The cumulative incidence of patient's hemorrhage and radiation necrosis was 4.92% (3/61) and 13.11% (8/61) after 'Sandwich treatment'. CONCLUSIONS: 'Sandwich treatment' strategy is safe and effective for LBM located in motor area. The strategy could rapidly improve the patients' movement and enhance their physical strength rehabilitation.

Two-Day Fraction Gamma Knife Radiosurgery for Large Brain Metastasis.

OBJECTIVE: We investigated how treating large brain metastasis (LBM) using 2-day fraction Gamma Knife radiosurgery (GKRS) affects tumor control and patient survival. A prescription dose of 10.3 Gy was applied for 2 consecutive days, with a biologically effective dose equivalent to a tumor single-fraction dose of 16.05 Gy and a brain single-fraction dose of 15.12 Gy. METHODS: Between November 2017 and December 2021, 42 patients (mean age, 68.3 years; range, 50-84 years; male, 29 [69.1%]; female, 13 [30.9%]) with 44 tumors underwent 2-day fraction GKRS to treat large volume brain metastasis. The main cancer types were non-small cell lung cancer (n=16), small cell lung cancer (n=7), colorectal cancer (n=7), breast cancer (n=3), gastric cancer (n=2), and other cancers (n=7). Twenty-one patients (50.0%) had a single LBM, 19 (46.3%) had a single LBM and other metastases, and two had two (4.7%) large brain metastases. At the time of the 2-day fraction GKRS, the tumors had a mean volume of 23.1 mL (range, 12.5-67.4). On each day, radiation was administered at a dose of 10.3 Gy, mainly using a 50% isodose-line. RESULTS: We obtained clinical and magnetic resonance imaging follow-up data for 34 patients (81%) with 35 tumors, who had undergone 2-day fraction GKRS. These patients did not experience acute or late radiation-induced complications during follow-up. The median and mean progression-free survival (PFS) periods were 188 and 194 days, respectively. The local control rates at 6, 9, and 12 months were 77%, 40%, and 34%, respectively. The prognostic factors related to PFS were prior radiotherapy (p=0.019) and lung cancer origin (p=0.041). Other factors such as tumor volumes, each isodose volumes, and peri-GKRS systemic treatment were not significantly related to PFS. The overall survival period of the 44 patients following repeat stereotactic radiosurgery (SRS) ranged from 15-878 days (median, 263±38 days; mean, 174±43 days) after the 2-day fraction GKRS. Eight patients (18.2%) were still alive. CONCLUSION: Considering the unsatisfactory tumor control, a higher prescription dose should be needed in this procedure as a salvage management. Moreover, in the treatment for LBM with fractionated SRS, using different isodoses and prescription doses at the treatment planning for LBMs should be important. However, this report might be a basic reference with the same fraction number and prescription dose in the treatment for LBMs with frame-based SRS.

[Results of hypofractionated stereotactic radiotherapy for resected and intact large brain metastases]. / Rezul'taty stereotaksicheskoi radioterapii v rezhime gipofraktsionirovaniya krupnykh metastazov v golovnom mozge posle khirurgicheskoi rezektsii i v samostoyatel'nom variante lecheniya.

Post-resection or isolated hypofractionated stereotactic radiotherapy (HF-SRT) is a therapeutic option for large brain metastases (>2 cm, LBMs). OBJECTIVE: To compare the results of post-resection or isolated HF-SRT in patients with LBMs. MATERIAL AND METHODS: A prospective study included 115 patients with 129 intact LBMs and 133 patients with 149 resected LBMs who underwent HF-SRT. Median baseline focal size was 22.5 and 28 mm, median target volume - 8.3 and 23.7 cm3, respectively. RESULTS: Median follow-up was 13.9 months, median overall survival - 19.1 months. After 12 months, local recurrences developed in 17 and 31% of patients, respectively (p=0.0078). Local recurrence after 12 months developed in 23% of patients with residual tumor in postoperative cavity compared to 16% of patients after total resection (p=0.0073). After 12 months, incidence of leptomeningeal progression was 27 and 11%, respectively (p=0.033), incidence of symptomatic radiation-induced necrosis - 4 and 23%, respectively (p=0.0006). CONCLUSION: Post-resection HF-SRT demonstrated better local control and less severe symptomatic radiation-induced necrosis compared to patients with intact LBMs. Incidence of leptomeningeal progression is significantly higher after resection of LBMs.

'Sandwich treatment' for posterior fossa brain metastases with volume larger than 4cm3: a multicentric retrospective study.

Single stereotactic radiosurgery (SRS) for posterior fossa brain metastases (BM) larger than 4cm3 is dangerous. 'Sandwich treatment' strategy was developed for these BMs. The strategy was one week treatment course which includes 2-stage SRS and using Bevacizumab once during SRS gap. Patients from four gamma knife center were retrospectively analyzed. The changes of tumor and peri-tumor edema volume were studied. The Dizziness Handicap Inventory (DHI) Vomiting Score (VS) and Glasgow Coma Scale (GCS) were used to evaluate patients' clinical symptom changes. Karnofsky performance scale (KPS) and Barthel Index (BI) were used to evaluate patients' overall fitness status and physical activity rehabilitation. Tumor local control (TLC) and patients' overall survival (OS) rate were also calculated. Forty patients with 45 LBMs received 'Sandwich treatment'. The mean edema volume reduced remarkably at the course of therapy and 3 months later (P < 0.01). The mean tumor volume greatly decreased 3 months later (P < 0.01). Patients' clinical symptoms that reflected by median score of DHI, VS, GCS were improved dramatically at the course of therapy and 3 months later (P < 0.01). Similar changes happened in median score of KPS and BI that reflected patients' overall fitness status and physical activity rehabilitation (P < 0.01). Patients' median OS was 14.3 months, with 95.4%, 76.2%, and 26.3% survival rate at 6, 12, 24 months. The TLC rate at 6, 12, 24 months was 97.5%, 86.0% and 62.2%.The 'Sandwich treatment' is safe and effective for patients with LBM over 4cm3 in the posterior fossa. The strategy could quickly improve patients' symptoms, well control tumor growth, prolong patient's OS, and has controllable side effects.

Up-front single-session radiosurgery for large brain metastases-volumetric responses and outcomes.

BACKGROUND: Patients presenting with large brain metastases (LBM) pose a management challenge to the multidisciplinary neuro-oncologic team. Treatment options include surgery, whole-brain or large-field radiation therapy (WBRT), stereotactic radiosurgery (SRS), or a combination of these. OBJECTIVE: To determine if corticosteroid therapy followed by SRS allows for efficient minimally invasive care in patients with LBMs not compromised by mass effect. METHODS: We analyzed the change in tumor volume to determine the efficacy of single-session SRS in the treatment of LBM in comparison to other treatment modalities. Twenty-nine patients with systemic cancer and brain metastasis (≥ 2.7 cm in greatest diameter) who underwent single-session SRS were included. RESULTS: Among 29 patients, 69% of patients had either lung, melanoma, or breast cancer. The median initial tumor size (maximal diameter) was 32 mm (range 28-43), and the median initial tumor volume was 9.56 cm3 (range 1.56-25.31). The median margin dose was 16 Gy (range 12-18). The average percent decrease in tumor volume compared to pre-SRS volume was 55% on imaging at 1-2 months, 58% at 3-5 months, 64% at 6-8 months, and 57% at > 8 months. There were no adverse events immediately following SRS. Median corticosteroid use after SRS was 21 days. Median survival after radiosurgery was 15 months. CONCLUSION: Initial high-dose corticosteroid therapy followed by prompt single-stage SRS is a safe and efficacious method to manage patients with LBMs (defined as ≥ 2.7 cm).

Evaluation of Biological Effective Dose in Gamma Knife Staged Stereotactic Radiosurgery for Large Brain Metastases.

Objective: Gamma knife (GK) staged stereotactic radiosurgery (Staged-SRS) has become an effective treatment option for large brain metastases (BMs); however, it has been challenging to evaluate the total dose because of tumor shrinkage between two staged sessions. This study aims to evaluate total biological effective dose (BED) in Staged-SRS, and to compare the BED with those in single-fraction SRS (SF-SRS) and hypo-fractionated SRS (HF-SRS). Methods: Patients treated with GK Staged-SRS at a single institution were retrospectively included. The dose delivered in two sessions of Staged-SRS was summed using the deformable image registration. Each patient was replanned for SF-SRS and HF-SRS. The total BEDs were computed using the linear-quadratic model. Tumor BED98% and brain V84Gy2, equivalent to V12Gy in SF-SRS, were compared between SF-SRS, HF-SRS, and Staged-SRS plans with the Wilcoxon test. Results: Twelve patients with 24 BMs treated with GK Staged-SRS were identified. We observed significant differences (p < 0.05) in tumor BED98% but comparable brain V84Gy2 (p = 0.677) between the Staged-SRS and SF-SRS plans. No dosimetric advantages of Staged-SRS over HF-SRS were observed. Tumor BED98% in the HF-SRS plans were significantly higher than those in the Staged-SRS plans (p < 0.05). Despite the larger PTVs, brain V84Gy2 in the HF-SRS plans remained lower (p < 0.05). Conclusion: We presented an approach to calculate the composite BEDs delivered to both tumor and normal brain tissue in Staged-SRS. Compared to SF-SRS, Staged-SRS delivers a higher dose to tumor but maintains a comparable dose to normal brain tissue. Our results did not show any dosimetric advantages of Staged-SRS over HF-SRS.

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

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

Factors correlating with survival following adjuvant or definitive radiosurgery for large brain metastases.

BACKGROUND: We sought to identify variates correlating with overall survival (OS) in patients treated with surgery (S) plus adjuvant stereotactic radiosurgery (SRS) versus definitive SRS for large (>4 cc) brain metastases (BrM). METHODS: We used univariate (UVA) and multivariate analyses (MVA) to identify survival correlates among eligible patients identified from a prospective registry and compared definitive SRS to S+ adjuvant SRS cohorts using propensity score-matched analysis (PSMA). Secondary outcomes were measured using the cumulative incidence (CI) method. RESULTS: We identified 364 patients; 127 and 237 were treated with S+SRS and definitive SRS, respectively. On UVA, SRS alone [HR1.73 (1.35,2.22) P < .001), BrM quantity [HR 1.13 (1.06-1.22) (P < .001)]; performance status (PS) [HR 2.78 (1.73-4.46) (P < .001)]; extracranial disease (ECD) [HR 1.82 (1.37,2.40) (P < .001)]; and receipt of systemic treatment after BrM therapy, [HR 0.58 (0.46-073) (P < .001)] correlated with OS. On MVA, SRS alone [HR 1.81 (1.19,2.74) (P < .0054)], SRS target volume [HR 1.03 (1.01,1.06) (P < .0042)], and receipt of systemic treatment [HR 0.68 (0.50,0.93) (P < .015)] correlated with OS. When PSMA was used to balance ECD, BrM quantity, PS, and SRS target volume, SRS alone remained correlated with worsened OS [HR 1.62 (1.20-2.19) (P = 0.0015)]. CI of local failure requiring resection at 12 months was 3% versus 7% for S+SRS and SRS cohorts, respectively [(HR 2.04 (0.89-4.69) (P = .091)]. CI of pachymeningeal failure at 12 months was 16% versus 0% for S+SRS and SRS. CONCLUSION: SRS target volume, receipt of systemic therapies, and treatment with S+SRS instead of definitive SRS correlated with improved survival in patients with large BrM.

Management Strategies for Large Brain Metastases.

Brain metastases represent the most common intracranial neoplasm and pose a significant disease burden on the individual and the healthcare system. Although whole brain radiation therapy was historically a first line approach, subsequent research and technological advancements have resulted in a larger armamentarium of strategies for treatment of these patients. While chemotherapeutic options remain limited, surgical resection and stereotactic radiosurgery, as well as their combination therapies, have shifted the paradigms for managing intracranial metastatic disease. Ultimately, no single treatment is shown to be consistently effective across patient groups in terms of overall survival, local and distant control, neurocognitive function, and performance status. However, close consideration of patient and tumor characteristics may help delineate more favorable treatment strategies for individual patients. Here the authors present a review of the recent literature surrounding surgery, whole brain radiation therapy, stereotactic radiosurgery, and combination approaches.

Clinical Outcomes and Prognostic Factors of Fractionated Stereotactic Radiosurgery for Brain Metastases ≥20 mm as a Potential Alternative to Surgery.

BACKGROUND: This study investigated the outcomes and prognostic factors of fractionated stereotactic radiosurgery (FSRS) for treatment of brain metastases (BMs) ≥20 mm and determined whether FSRS could replace surgery, the primary treatment for large BMs. METHODS: Patients with BMs ≥20 mm treated with FSRS were retrospectively examined. Patients who underwent FSRS postoperatively were excluded. Local failure, intracranial failure, and adverse events were evaluated. RESULTS: Overall, 116 lesions in 105 patients were evaluated. The performance status was 0-1, 2-4, and unknown for 86, 28, and 2 patients, respectively. The median maximum tumor diameter was 25 mm, and the median prescribed dose was 35 Gy in 3 fractions. The median follow-up period after FSRS was 8 months. The 1-year local failure, intracranial failure, and overall survival rates were 12.5%, 56.6%, and 49.0%, respectively. A maximum dose of ≥135 Gy (biological equivalent dose [α/ß = 10 Gy]) and good performance status were independent favorable prognostic factors for local control. After FSRS, 21 (20%) patients were treated with whole-brain radiotherapy because of multiple intracranial recurrences, and 4 (3.4%) patients underwent surgery because of local recurrence. CONCLUSIONS: FSRS for BMs ≥20 mm achieved good local control. Only 3.4% of patients required surgery after FSRS, suggesting that FSRS is a potential alternative to surgery. For FSRS, a higher maximum tumor dose was useful for local control.

Metastatic Neoplasm Volume Kinetics Following 2-Stage Stereotactic Radiosurgery.

BACKGROUND: Multisession staged stereotactic radiosurgery (SRS) represents an alternative approach for management of large brain metastases (LBMs), with potential advantages over fractionated SRS. This study investigated clinical efficacy and safety of 2-stage stereotactic radiosurgery (2-SSRS) in patients with LBMs. METHODS: Patients with LBMs treated with 2-SSRS between 2014 and 2020 were evaluated. Demographic, clinical, and radiologic data were obtained. Volumetric measurements at first SRS session, second SRS session, and follow-up imaging studies were obtained. Characteristics that might predict response to 2-SSRS were evaluated through Fisher exact or Mann-Whitney U test. RESULTS: The study included 24 patients with 26 LBMs. Median (range) marginal doses for first and second SRS sessions were 15 Gy (14-18 Gy) and 15 Gy (12-16 Gy), respectively. Median (range) tumor volumes at first SRS session, second SRS session, and 3-month follow-up were 8.1 cm3 (1.5-28.5 cm3), 3.3 cm3 (0.8-26.1 cm3), and 2.2 cm3 (0.2-10.1 cm3), respectively. Of 26 lesions, 24 (92%) demonstrated early local control following the first SRS session, with 17 lesions (71%) demonstrating a decrease of ≥30% in T1 postcontrast MRI volume before the second SRS session and 3 lesions (12%) remaining stable. Eventually, 4 lesions showed disease progression after 2-SSRS. The median time to local progression was not reached; the median time to intracranial progression was 9.1 months. CONCLUSIONS: Our study supports the effectiveness and safety of 2-SSRS as a treatment modality for patients with LBMs, especially in poor surgical candidates. The local failure rate and low occurrence of adverse effects are comparable to other staged radiosurgery studies.

Single- and hypofractionated stereotactic radiosurgery for large (> 2 cm) brain metastases: a systematic review.

PURPOSE: Since frameless stereotactic radiosurgery (SRS) techniques have been recently introduced, hypofractionated SRS (HF-SRS) for large brain metastases (BMs) is gradually increasing. To verify the efficacy and safety of HF-SRS for large BMs, we aimed to perform a systematic review and compared them with SF-SRS. METHODS: We systematically searched the studies regarding SF-SRS or HF-SRS for large (> 2 cm) BM from databases including PubMed, Embase, and the Cochrane Library on July 31, 2018. Biologically effective dose with the α/ß ratio of 10 (BED10), 1-year local control (LC), and radiation necrosis (RN) were compared between the two groups, with the studies being weighted by the sample size. RESULTS: The 15 studies with 1049 BMs that described 1-year LC and RN were included. HF-SRS tended to be performed in larger tumors; however, higher mean BED10 (50.1 Gy10 versus 40.4 Gy10, p < 0.0001) was delivered in the HF-SRS group, which led to significantly improved 1-year LC (81.6 versus 69.0%, p < 0.0001) and 1-year overall survival (55.1 versus 47.2%, p < 0.0001) in the HF-SRS group compared to the SF-SRS group. In contrast, the incidence of radiation toxicity was significantly decreased in the HF-SRS group compared to the SF-SRS group (8.0 versus 15.6%, p < 0.0001). CONCLUSION: HF-SRS results in better LC of large BMs while simultaneously reducing RN compared to SF-SRS. Thus, HF-SRS should be considered a priority for SF-SRS in patients with large BMs who are not suitable to undergo surgical resection.

Staged Stereotactic Radiosurgery Decreases Symptomatic Radionecrosis in Large Brain Metastasis.

BACKGROUND: Limited brain metastasis is treated definitively with stereotactic radiosurgery when surgical resection is not indicated. Although this has historically been performed in a single fraction, multi-fraction approaches such as fraction radiosurgery (FSRS) and staged radiosurgery (SSRS) have been recently examined as alternative approaches for larger lesions to permit better tumor control without increased toxicity. CASE REPORT: We present the case of a patient who developed symptomatic radionecrosis in two brain metastasis, 2.3 cm and 2.1 cm in size, which were treated with 18 Gy in one fraction, but no radionecrosis in a 3.3 cm lesion treated in two fractions of 15 Gy nor in two punctate lesions that were treated in one fraction of 20 Gy. Although she did not respond to steroids, she responded to bevacizumab symptomatically and on neuroimaging. CONCLUSION: Congruent with other recent studies, our report suggests that large brain metastasis should be considered for FSRS/SSRS.

Linac-based fractionated stereotactic radiotherapy with a micro-multileaf collimator for large brain metastasis unsuitable for surgical resection.

The aim of this study was to assess clinical outcomes using linac-based, fractionated, stereotactic radiotherapy (fSRT) with a micro-multileaf collimator for large brain metastasis (LBM) unsuitable for surgical resection. Between January 2009 and October 2018 we treated 21 patients with LBM using linac-based fSRT. LBM was defined as a tumor with ≥30 mm maximal diameter in gadolinium-enhanced magnetic resonance images. LBMs originated from the lung (n = 17, 81%), ovary (n = 2, 9.5%), rectum (n = 1, 4.8%) and esophagus (n = 1, 4.8%). The median pretreatment Karnofsky performance status was 50 (range: 50-80). Recursive partition analysis (RPA) was as follows: Classes 2 and 3 were 7 and 14 patients, respectively. The median follow-up was 5 months (range: 1-86 months). The range of tumor volume was 8.7-26.5 cm3 (median: 17.1 cm3). All patients were basically treated with 35Gy in 5 fractions, except in three cases. The progression-free survival was 3.0 months. The median survival time was 7.0 months. There was no permanent radiation injury in any of the patients. Radiation-caused central nervous system necrosis, according to the Common Terminology Criteria for Adverse Events version 4.0, occurred in one patient (grade 3). One patients received bevacizumab for radiation necrosis. Two patients underwent additional surgical resection due to local progression and cyst formation. For patients with LBM unsuitable for surgical resection, linac-based fSRT is a promising therapeutic alternative.

Comparison of two-stage Gamma Knife radiosurgery outcomes for large brain metastases among primary cancers.

PURPOSE: Stereotactic radiosurgery (SRS) is typically considered for patients who cannot undergo surgical resection for large (> 10 cm3) brain metastases (BMs). Staged SRS requires adaptive planning during each stage of the irradiation period for improved tumor control and reduced radiation damage. However, there has been no study on the tumor reduction rates of this method. We evaluated the outcomes of two-stage SRS across multiple primary cancer types. METHODS: We analyzed 178 patients with 182 large BMs initially treated with two-stage SRS. The primary cancers included breast (BC), non-small cell lung (NSCLC), and gastrointestinal tract cancers (GIC). We analyzed the overall survival (OS), neurological death, systemic death (SD), tumor progression (TP), tumor recurrence (TR), radiation necrosis (RN), and the tumor reduction rate during both stages. RESULTS: The median survival time after the first Gamma Knife surgery (GKS) procedure was 6.6 months. Compared with patients with BC and NSCLC, patients with GIC had shorter OS and a higher incidence of SD. Compared with patients with NSCLC and GIC, patients with BC had significantly higher tumor reduction rates in both sessions. TP rates were similar among primary cancer types. There was no association of the tumor reduction rate with tumor control. The overall cumulative incidence of RN was 4.2%; further, the RN rates were similar among primary cancer types. CONCLUSIONS: Two-stage SRS should be considered for BC and NSCLC if surgical resection is not indicated. For BMs from GIC, staged SRS should be carefully considered and adapted to each unique case given its lower tumor reduction rate and shorter OS.

The Judicious Use of Stereotactic Radiosurgery and Hypofractionated Stereotactic Radiotherapy in the Management of Large Brain Metastases.

Brain metastases are the most common intracranial malignant tumor in adults and are a cause of significant morbidity and mortality for cancer patients. Large brain metastases, defined as tumors with a maximum dimension >2 cm, present a unique clinical challenge for the delivery of stereotactic radiosurgery (SRS) as patients often present with neurologic symptoms that require expeditious treatment that must also be balanced against the potential consequences of surgery and radiation therapy-namely, leptomeningeal disease (LMD) and radionecrosis (RN). Hypofractionated stereotactic radiotherapy (HSRT) and pre-operative SRS have emerged as novel treatment techniques to help improve local control rates and reduce rates of RN and LMD for this patient population commonly managed with post-operative SRS. Recent literature suggests that pre-operative SRS can potentially half the risk of LMD compared to post-operative SRS and that HSRT can improve risk of RN to less than 10% while improving local control when meeting the appropriate goals for biologically effective dose (BED) and dose-volume constraints. We recommend a 3- or 5-fraction regimen in lieu of SRS delivering 15 Gy or less for large metastases or resection cavities. We provide a table comparing the BED of commonly used SRS and HSRT regimens, and provide an algorithm to help guide the management of these challenging clinical scenarios.

Surgical resection and postoperative radiosurgery versus staged radiosurgery for large brain metastases.

PURPOSE: The purpose of this study was to retrospectively evaluate the new treatment paradigm of staged stereotactic radiosurgery (SRS) for the treatment of large brain metastases (BM) compared to the standard of surgical resection followed by SRS. METHODS: We evaluated 78 patients with large BM treated 2012-2017 with surgical resection and postoperative SRS (surgery + SRS) or staged SRS separated by 1 month. Overall survival (OS) was estimated using the Kaplan Meier method and compared across groups using the log-rank test. Cumulative incidence of neurologic death and local and distant brain failure (LF, DBF) were estimated using competing risk methodology. RESULTS: Forty patients were treated with surgery + SRS and 38 patients were treated with staged SRS. Median follow-up was 23.2 months (95% CI 20.5-39.3). Median OS was 13.2 months for staged SRS compared to surgery + SRS 9.7 months (p = 0.53). Cumulative incidence of neurologic death at 1 year was 23% after surgery + SRS, 27% after staged SRS (p = 0.69); cumulative incidence of LF at 1 year was 6% and 8% (p = 0.65) and 1-year DBF was 59% and 21% (p ≤ 0.01). Overall rates of leptomeningeal failure and radiation necrosis were similar between the groups (p = 0.63 and p = 1.0). CONCLUSIONS: Though surgery and postoperative SRS is the standard, staged SRS represents an attractive treatment paradigm for treating large BM without sacrificing LC or survival, and potentially decreases DBF. Prospective studies are needed to validate these findings.