Nivolumab plus ipilimumab with chemotherapy for non-small cell lung cancer with untreated brain metastases: A multicenter single-arm phase 2 trial (NIke, LOGiK 2004).

BACKGROUND: The effect of dual immunotherapy combined with platinum-based chemotherapy on untreated brain metastases derived from non-small cell lung cancer (NSCLC) has remained unclear. METHODS: This multicenter single-arm phase 2 study enrolled patients with chemotherapy-naïve advanced NSCLC and at least one brain metastasis ≥ 5 mm in size that had not been previously treated. Patients received nivolumab plus ipilimumab combined with platinum-doublet chemotherapy (two cycles), followed by nivolumab-ipilimumab alone. The primary endpoint of the study was intracranial response rate as determined by modified Response Evaluation Criteria in Solid Tumors (RECIST) for brain metastases of ≥ 5 mm as target lesions. RESULTS: A total of 30 patients from 18 institutions was enrolled in this study. The median age was 66.5 years (range, 47-83 years), and 26 patients (87 %) had a non-squamous cell carcinoma histology. The median size of all target brain lesions was 8.4 mm, with a range of 5-39 mm. The intracranial response rate assessed by modified RECIST was 50.0 % (95 % CI, 33.2-66.8 %), with the rate of complete response being 20.0 %, and the study met its primary endpoint. The systemic response rate was 53.3 % (95 % CI, 36.1-69.8 %), and responses for intracranial and extracranial lesions were generally consistent. The median intracranial progression-free survival was 8.1 months, and both the median intracranial duration of response and time to brain radiotherapy were not reached. CONCLUSION: Nivolumab plus ipilimumab combined with platinum-based chemotherapy showed promising intracranial activity in NSCLC patients with untreated brain metastases. TRIAL REGISTRATION: jRCT071210019.

Preoperative stereotactic radiotherapy for the management of brain metastases.

Traditionally, postoperative whole-brain radiation therapy (WBRT) has been used for resected brain metastases, reducing local and intracerebral relapses. However, WBRT is associated with cognitive deterioration. Postoperative stereotactic radiotherapy (SRT) has emerged due to its neurocognitive preservation benefits. Despite its advantages, postoperative SRT has several drawbacks, including difficulties in target volume delineation, increased risk of radionecrosis (RN) and leptomeningeal disease (LMD), and prolonged treatment duration. Preoperative SRT has been proposed as a potential alternative, offering promising results in retrospective studies. Retrospective studies have suggested that preoperative SRT could achieve high local control rates with fewer LMD and RN rates compared to postoperative SRT. However, preoperative SRT is primarily based on retrospective data, and no phase 2/3 trials have been published to date. Ongoing clinical trials are expected to provide further insights into the efficacy and safety of preoperative SRT, addressing key questions regarding fractionation, dose, and timing relative to surgery.

Genomic signature for oligometastatic disease in non-small cell lung cancer patients with brain metastases.

Purpose/objectives: Biomarkers for extracranial oligometastatic disease remain elusive and few studies have attempted to correlate genomic data to the presence of true oligometastatic disease. Methods: Patients with non-small cell lung cancer (NSCLC) and brain metastases were identified in our departmental database. Electronic medical records were used to identify patients for whom liquid biopsy-based comprehensive genomic profiling (Guardant Health) was available. Extracranial oligometastatic disease was defined as patients having ≤5 non-brain metastases without diffuse involvement of a single organ. Widespread disease was any spread beyond oligometastatic. Fisher's exact tests were used to screen for mutations statistically associated (p<0.1) with either oligometastatic or widespread extracranial disease. A risk score for the likelihood of oligometastatic disease was generated and correlated to the likelihood of having oligometastatic disease vs widespread disease. For oligometastatic patients, a competing risk analysis was done to assess for cumulative incidence of oligometastatic progression. Cox regression was used to determine association between oligometastatic risk score and oligoprogression. Results: 130 patients met study criteria and were included in the analysis. 51 patients (39%) had extracranial oligometastatic disease. Genetic mutations included in the Guardant panel that were associated (p<0.1) with the presence of oligometastatic disease included ATM, JAK2, MAP2K2, and NTRK1, while ARID1A and CCNE1 were associated with widespread disease. Patients with a positive, neutral and negative risk score for oligometastatic disease had a 78%, 41% and 11.5% likelihood of having oligometastatic disease, respectively (p<0.0001). Overall survival for patients with positive, neutral and negative risk scores for oligometastatic disease was 86% vs 82% vs 64% at 6 months (p=0.2). Oligometastatic risk score was significantly associated with the likelihood of oligoprogression based on the Wald chi-square test. Patients with positive, neutral and negative risk scores for oligometastatic disease had a cumulative incidence of oligometastatic progression of 77% vs 35% vs 33% at 6 months (p=0.03). Conclusions: Elucidation of a genomic signature for extracranial oligometastatic disease derived from non-invasive liquid biopsy appears feasible for NSCLC patients. Patients with this signature exhibited higher rates of early oligoprogression. External validation could lead to a biomarker that has the potential to direct local therapies in oligometastatic patients.

First-line treatment of EGFR-mutated non-small cell lung cancer with brain metastases: a systematic review and meta-analysis.

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433-0.973) and 0.682 (95% CI: 0.464-0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511-1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14-3.4) and PFS 2.13 (95% CI: 1.28-3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation.

Factors associated with the distribution of brain metastases in lung cancer: a retrospective study.

The distribution of brain metastases (BMs) in patients with lung cancer may be associated with the primary tumor-related factors and cerebral small vascular diseases (CSVDs). The aim of this study was to investigate the potential effects of the above factors on the distribution of BMs. A total of 5,788 lesions in 823 patients with BMs from lung cancer were enrolled. The numbers of BMs and CSVDs in 15 brain regions were determined. CSVDs include recent small subcortical infarcts (RSSIs), perivascular spaces, and lacunes of presumed vascular origin (LPVOs). We collected the number of CSVDs, and primary tumor-related factors (including clinical and imaging features) in lung cancer patients with BMs. Univariate and multivariate linear regression were utilized to analyze the potential influence of the above factors on the number of BMs in 15 brain regions. In addition, we performed subgroup analyses of all patients with adenocarcinoma (AD), female patients with AD, male patients with AD, and patients with small cell lung cancer. Univariate linear regression analyses showed that bone metastasis, adrenal metastasis, RSSIs, and LPVOs were associated with the number of BMs in over half of the examined brain regions. Only the independent association of LVPOs persisted in the multivariate linear regression analyses, and similar phenomenon was found in the subgroup analyses. In conclusion, the distribution of BMs in lung cancer patients appears to be associated with the presence of LVPOs, while primary tumor-related factors have less influence.

2.5D deep learning based on multi-parameter MRI to differentiate primary lung cancer pathological subtypes in patients with brain metastases.

BACKGROUND: Brain metastases (BMs) represents a severe neurological complication stemming from cancers originating from various sources. It is a highly challenging clinical task to accurately distinguish the pathological subtypes of brain metastatic tumors from lung cancer (LC).The utility of 2.5-dimensional (2.5D) deep learning (DL) in distinguishing pathological subtypes of LC with BMs is yet to be determined. METHODS: A total of 250 patients were included in this retrospective study, divided in a 7:3 ratio into training set (N=175) and testing set (N=75). We devised a method to assemble a series of two-dimensional (2D) images by extracting adjacent slices from a central slice in both superior-inferior and anterior-posterior directions to form a 2.5D dataset. Multi-Instance learning (MIL) is a weakly supervised learning method that organizes training instances into "bags" and provides labels for entire bags, with the purpose of learning a classifier based on the labeled positive and negative bags to predict the corresponding class for an unknown bag. Therefore, we employed MIL to construct a comprehensive 2.5D feature set. Then we used the single-slice as input for constructing the 2D model. DL features were extracted from these slices using the pre-trained ResNet101. All feature sets were inputted into the support vector machine (SVM) for evaluation. The diagnostic performance of the classification models were evaluated using five-fold cross-validation, with accuracy and area under the curve (AUC) metrics calculated for analysis. RESULTS: The optimal performance was obtained using the 2.5D DL model, which achieved the micro-AUC of 0.868 (95% confidence interval [CI], 0.817-0.919) and accuracy of 0.836 in the test cohort. The 2D model achieved the micro-AUC of 0.836 (95 % CI, 0.778-0.894) and accuracy of 0.827 in the test cohort. CONCLUSIONS: The proposed 2.5D DL model is feasible and effective in identifying pathological subtypes of BMs from lung cancer.

In vivo characterization of brain tumor biomechanics: magnetic resonance elastography in intracranial B16 melanoma and GL261 glioma mouse models.

Introduction: Magnetic Resonance Elastography (MRE) allows the non-invasive quantification of tumor biomechanical properties in vivo. With increasing incidence of brain metastases, there is a notable absence of appropriate preclinical models to investigate their biomechanical characteristics. Therefore, the purpose of this work was to assess the biomechanical characteristics of B16 melanoma brain metastases (MBM) and compare it to murine GL261 glioblastoma (GBM) model using multifrequency MRE with tomoelastography post processing. Methods: Intracranial B16 MBM (n = 6) and GL261 GBM (n = 7) mouse models were used. Magnetic Resonance Imaging (MRI) was performed at set intervals after tumor implantation: 5, 7, 12, 14 days for MBM and 13 and 22 days for GBM. The investigations were performed using a 7T preclinical MRI with 20 mm head coil. The protocol consisted of single-shot spin echo-planar multifrequency MRE with tomoelastography post processing, contrast-enhanced T1- and T2-weighted imaging and diffusion-weighted imaging (DWI) with quantification of apparent diffusion coefficient of water (ADC). Elastography quantified shear wave speed (SWS), magnitude of complex MR signal (T2/T2*) and loss angle (φ). Immunohistological investigations were performed to assess vascularization, blood-brain-barrier integrity and extent of glucosaminoglucan coverage. Results: Volumetric analyses displayed rapid growth of both tumor entities and softer tissue properties than healthy brain (healthy: 5.17 ± 0.48, MBM: 3.83 ± 0.55, GBM: 3.7 ± 0.23, [m/s]). SWS of MBM remained unchanged throughout tumor progression with decreased T2/T2* intensity and increased ADC on days 12 and 14 (p<0.0001 for both). Conversely, GBM presented reduced φ values on day 22 (p=0.0237), with no significant alterations in ADC. Histological analysis revealed substantial vascularization and elevated glycosaminoglycan content in both tumor types compared to healthy contralateral brain. Discussion: Our results indicate that while both, MBM and GBM, exhibited softer properties compared to healthy brain, imaging and histological analysis revealed different underlying microstructural causes: hemorrhages in MBM and increased vascularization and glycosaminoglycan content in GBM, further corroborated by DWI and T2/T2* contrast. These findings underscore the complementary nature of MRE and its potential to enhance our understanding of tumor characteristics when used alongside established techniques. This comprehensive approach could lead to improved clinical outcomes and a deeper understanding of brain tumor pathophysiology.

Brain metastases from esophageal cancer: A retrospective review from a single institution.

PURPOSE: Patients with brain metastases (BrM) from esophageal cancer have poor prognosis, the incidence of which is expected to rise due to improved survival from the primary tumor and increased neuroimaging. We aimed to identify patient and esophageal cancer characteristics associated with shorter survival in patients with BrM and, secondly, to compare the prognosis of patients with HER2 overexpression. METHODS: We retrospectively reviewed patients with BrM from esophageal cancer at a single institution from 2008-2021. We collected patient demographics, primary tumor and BrM characteristics, and treatment. Our primary outcome was median survival from the time of BrM. RESULTS: The median age at primary diagnosis was 66.5 years and 86% were male. Of the 49 patients, 71% had adenocarcinoma, 20% squamous cell carcinoma and 8% other. 71% of patients presented with stage III or IV disease, including 16% with synchronous primary and BrM. The median time to BrM was 10.1 months (IQR 1.7-22.8) and the median survival from BrM was 8.4 months (95%CI 4.8-16.8). On multivariable analysis, treatment with stereotactic radiosurgery (HR=0.19;p=0.04), surgical resection (HR 0.24;p=0.03) and immunotherapy (HR 0.19;p=0.04) were associated with increased survival while KPS ≤70 (HR=13.2;p<0.001) was associated with decreased survival. HER2 overexpression was found in 22% of patients, but we noted no survival difference (5.2 months HER2+ versus 9.8 months HER2neg;p=0.95). CONCLUSION: The median survival from esophageal-to-brain metastasis was 8.4 months. Patients with a single lesion, KPS score >70, and treatment with surgical resection was correlated with improved survival. Further, HER2+ patients had distinct patient and BrM characteristics.

Unmasking the Intruder: A Case of Lung Carcinoma Mimicking As Glioma.

Lung carcinoma with metastases to the brain typically involves the cerebral hemispheres, occasionally the cerebellum and rarely the brainstem. This report presents the case of a 73-year-old male who complained of neurological symptoms of left-sided limb weakness and was initially diagnosed with a high-grade glioma. With further radiological investigations, our patient was found to have primary bronchogenic carcinoma with metastasis to the brain. He underwent craniotomy with decompression of the mass and is currently undergoing chemotherapy. This case calls for the collaborative effort needed to diagnose brain metastases and the importance of histopathology for confirmation of the same.

An Exploratory Analysis of the Conditional Neurocognitive Function Failure Risk in Patients Receiving Whole Brain Radiotherapy for Brain Metastases on NRG Oncology CC001: Conditional Neurocognitive Toxicity Risk.

PURPOSE: We sought to estimate the conditional risk of development of neurocognitive function failure (NCFF) after whole brain radiotherapy (WBRT) for patients with brain metastases (BM) on NRG Oncology CC001. In addition, we aimed to determine if factors prognostic of NCFF at time of treatment remained relevant over time. MATERIALS/METHODS: We performed a post hoc analysis of 518 patients enrolled on NRG CC001 in which patients with BM were randomly assigned to WBRT + memantine or hippocampal-avoidant (HA-WBRT) + memantine. Life table method was used to calculate conditional monthly hazard rates and cumulative incidence was used to estimate rates of NCFF. Risk factors associated with NCFF were analyzed using cause-specific multivariable Cox proportional hazards modeling. RESULTS: The cumulative risk of development of NCFF by 6 months was 64.0% for the entire cohort. The greatest conditional monthly hazard rate of development of neurocognitive toxicity was 2-3 months post radiation (0.97, 95% CI 0.85-1.10); this rate significantly declined and then plateaued to 0.036 (95% CI: 0-0.11) by 8 months post treatment. For 2-month survivorship without cognitive failure, HA-WBRT (HR 0.74, P=0.033) and age ≤ 61 (HR 0.62, P=0.003) continued to be protective against cognitive toxicity. In addition, conditional cumulative incidence of development of NCFF was significantly reduced with HA techniques for patients living ≥ 2 months free of cognitive dysfunction (P=0.047). CONCLUSIONS: Our data highlight that the greatest risk for development of neurocognitive toxicity is within the first 3 months after treatment, and therefore strategies to mitigate toxicities should focus on this initial period. Moreover, the conditional risk of neurocognitive impairment significantly declines the longer patients live with preserved cognition. Importantly, these data can be used to inform patients on how their risks of development of NCFF can change over time.

Stereotactic Radiosurgery for 1-10 Brain Metastases to avoid Whole-Brain Radiotherapy - Results of the CYBER-SPACE Randomized Phase 2 Trial.

BACKGROUND: Stereotactic Radiosurgery (SRS) is an emerging alternative to whole-brain radiotherapy (WBRT) for treating multiple brain metastases (BM), reducing toxicity and improving tumor control. The CYBER-SPACE trial compared SRS based on either SPACE or MPRAGE MRI sequence for avoiding or delaying WBRT in patients with 1-10 BM. METHODS: Patients with 1-10 untreated BM were randomized 1:1 to receive SRS of all lesions based on either SPACE or MPRAGE MRI sequences. If subsequently new BM occurred, SRS was repeated. WBRT was indicated upon occurrence of >10 new BM, leptomeningeal disease or exhausted SRS-radiotolerance. The primary outcome was freedom from WBRT indication (WBRTi). Secondary outcomes included overall survival (OS), safety, and quality of life. RESULTS: 202 patients were randomized; SPACE n=99, MPRAGE n=103. 12-month WBRTi-free survival was 77.1% (95%-CI: 69.5%-83.1%) overall, 78.5% (95%-CI: 66.7%-86.5%) for SPACE, and 76.0% (95%-CI: 65.2%-83.9%) for MPRAGE (HR=0.84, 95%-CI: 0.43-1.63, p=0.590). Patients with 5-10 BM had shorter WBRTi-free survival (HR=3.13, 95%-CI: 1.53-6.40, p=0.002). Median OS was 13.1 months overall, 10.5 months for SPACE, and 15.2 months for MPRAGE (HR=1.10, 95%-CI: 0.78-1.56, p=0.585). Neurologic death rate was 10.1%. Predictors for longer OS included Karnofsky Performance Status >80% (HR=0.51, 95%-CI: 0.33-0.77, p=0.002) and concurrent immunotherapy (HR=0.34, 95%-CI: 0.23-0.52, p<0.001). CONCLUSIONS: The more sensitive SPACE sequence did not improve outcomes over MPRAGE. SRS with thorough monitoring and immediate re-treatment for new lesions decreases the need for WBRT and achieves low neurologic death rates. SRS should be considered a favorable alternative to WBRT for patients with 1-10 BM.

Case report: outcome of anlotinib treatment in breast cancer patient with brain metastases.

Brain metastases (BM) represent a common and severe complication of breast cancer (BC), emerging in approximately 10%-16% of all BC patients. The prevalent approach for treating BC patients with BM encompasses a multimodal strategy, combining surgery, whole brain radiation therapy, and stereotactic radiosurgery. Yet, a concrete guideline for localized treatment strategies remains elusive, while systemic treatments like small-molecule-targeted therapy and immunotherapy are still in the clinical trial phase. This case study presents a significant clinical response to anlotinib treatment in a patient with estrogen receptor-negative, progesterone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, complicated by BM. After the standard first-line treatment including albumin-bound paclitaxel, trastuzumab and pertuzumab, and a second-line treatment involving pyrotinib, capecitabine, and radiotherapy did not produce the desired results, the patient was then administered anlotinib in combination with pyrotinib and letrozole as a third-line treatment, which led to a partial response (PR). The findings suggest that anti-angiogenic therapy, specifically anlotinib, could be regarded as a promising therapeutic option for BC patients with BM.

Efficacy of Prophylactic Cranial Irradiation in Early to Mid-stage Small Cell Lung Cancer Patients in the Era of Magnetic Resonance Imaging.

BACKGROUND: Recent advancements in magnetic resonance imaging (MRI) for staging have highlighted the critical question of the need for prophylactic cranial irradiation (PCI) in managing early to mid-stage small cell lung cancer (SCLC). This study assesses the impact of PCI on overall survival (OS) and intracranial control among patients with stage I-IIB SCLC. METHODS: Data from 148 stage I-IIB SCLC patients treated with thoracic radiation therapy (TRT) at two centers were examined. Patients were categorized based on PCI administration: 63 received PCI, while 85 did not. All underwent pretreatment MRI, achieving at least a partial response to therapy. A 1:1 propensity score matching analysis corrected for potential biases. RESULTS: Propensity scores were generated to 116 patients, considering patient demographics, disease progression, and treatment methods. Death was included as a competing risk. The 3-year brain metastases (BM) occurrence rate was significantly higher in patients who did not receive PCI (30.0%) compared to those who did (14.8%), however, the difference was not statistically significant (No PCI vs. PCI, hazard ratio [HR]: 2.08, 95% CI [0.93-4.55], P = .07). No significant effect of PCI on OS was observed [PCI vs. No PCI, HR: 0.80, 95% CI (0.45-1.43), P = .45]. A subgroup analysis of stage IIB patients showed a significant increase in BM risk and mortality for those not receiving PCI (No PCI vs. PCI, BM risk HR: 5.85, 95% CI: 1.83-18.87, P = .003; mortality HR: 2.78, 95% CI: 1.14-6.67, P = .02), with less pronounced effects in stages I-IIA. CONCLUSION: With modern MRI-based screening, PCI may markedly benefit stage IIB SCLC patients by reducing BM and improving OS after initial sensitive treatment. This benefit does not appear to extend to stage I-IIA patients.

Optimization of sub-arc collimator angles in volumetric modulated arc therapy: a heatmap-based blocking index approach for multiple brain metastases.

To develop and assess an automated Sub-arc Collimator Angle Optimization (SACAO) algorithm and Cumulative Blocking Index Ratio (CBIR) metrics for single-isocenter coplanar volumetric modulated arc therapy (VMAT) to treat multiple brain metastases. This study included 31 patients with multiple brain metastases, each having 2 to 8 targets. Initially, for each control point, the MLC blocking index was calculated at different collimator angles, resulting in a two-dimensional heatmap. Optimal sub-arc segmentation and collimator angle optimization were achieved using an interval dynamic programming algorithm. Subsequently, VMAT plans were designed using two approaches: SACAO and the conventional Full-Arc Fixed Collimator Angle. CBIR was calculated as the ratio of the cumulative blocking index between the two plan approaches. Finally, dosimetric and planning parameters of both plans were compared. Normal brain tissue, brainstem, and eyes received better protection in the SACAO group (P < 0.05).Query Notable reductions in the SACAO group included 11.47% in gradient index (GI), 15.03% in monitor units (MU), 15.73% in mean control point Jaw area (AJaw,mean), and 19.14% in mean control point Jaw-X width (WJaw-X,mean), all statistically significant (P < 0.001). Furthermore, CBIR showed a strong negative correlation with the degree of plan improvement. The SACAO method enhanced protection of normal organs while improving transmission efficiency and optimization performance of VMAT. In particular, the CBIR metrics show promise in quantifying the differences specifically in the 'island blocking problem' between SACAO and conventional VMAT, and in guiding the enhanced application of the SACAO algorithm.

Predicting the T790M mutation in non-small cell lung cancer (NSCLC) using brain metastasis MR radiomics: a study with an imbalanced dataset.

BACKGROUND: Early detection of T790M mutation in exon 20 of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients with brain metastasis is crucial for optimizing treatment strategies. In this study, we developed radiomics models to distinguish NSCLC patients with T790M-positive mutations from those with T790M-negative mutations using multisequence MR images of brain metastasis despite an imbalanced dataset. Various resampling techniques and classifiers were employed to identify the most effective strategy. METHODS: Radiomic analyses were conducted on a dataset comprising 125 patients, consisting of 18 with EGFR T790M-positive mutations and 107 with T790M-negative mutations. Seventeen first- and second-order statistical features were selected from CET1WI, T2WI, T2FLAIR, and DWI images. Four classifiers (logistic regression, support vector machine, random forest [RF], and extreme gradient boosting [XGBoost]) were evaluated under 13 different resampling conditions. RESULTS: The area under the curve (AUC) value achieved was 0.89, using the SVM-SMOTE oversampling method in combination with the XGBoost classifier. This performance was measured against the AUC reported in the literature, serving as an upper-bound reference. Additionally, comparable results were observed with other oversampling methods paired with RF or XGBoost classifiers. CONCLUSIONS: Our study demonstrates that, even when dealing with an imbalanced EGFR T790M dataset, reasonable predictive outcomes can be achieved by employing an appropriate combination of resampling techniques and classifiers. This approach has significant potential for enhancing T790M mutation detection in NSCLC patients with brain metastasis.

Preoperative stereotactic radiosurgery for patients with 1-4 brain metastases: A single-arm phase 2 trial outcome analysis (NCT03398694).

Background: Stereotactic radiosurgery (SRS) following surgical resection is the standard of care for patients with symptomatic oligo brain metastasis (BM), however, it is associated with 10-15% local failure. Targeting a resection cavity is imprecise, thus preoperative radiosurgery where the target is well-defined may be superior, however, the efficacy of preoperative SRS has not yet been tested in a clinical trial. Methods: We conducted a phase 2, single-arm trial of preoperative SRS followed by surgical resection in patients with 1-4 symptomatic oligo BMs (NCT03398694) with the primary objective of measuring 6-month local control (LC). SRS was delivered to all patients utilizing a gamma knife or linear accelerator as per RTOG-9005 dosing criteria [Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47(2):291-298] based on tumor diameter with the exception that the largest lesion diameter treated was 5 cm with 15 Gy with all SRS treatment given in single fraction dosing. Results: The trial screened 50 patients, 48 patients were treated under the protocol and 32 patients completed the entire follow-up period. Of all the patients who completed the follow-up period, the primary endpoint of 6-month LC was 100% (95% CI: 0.891-1.000; P = .005). Secondary endpoints, presented as medians, were overall survival (17.6 months), progression-free survival (5.3 months), distant in-brain failure (40.8% at 1 year), leptomeningeal failure (4.8% at 1 year), and radiation necrosis (7.7% at 1 year). Conclusions: Our data confirms superior local control in patients who received preoperative SRS when compared to historical controls. Further study with a larger randomized cohort of patients is warranted to fully understand the benefits of preoperative SRS.

Progress of intracranial metastases during the interval before stereotactic radiosurgery, a retrospective cohort analysis.

INTRODUCTION: The incidence of intracranial metastatic disease is increasing worldwide. As a valuable treatment modality, stereotactic radiosurgery requires detailed imaging, and this study evaluated the differences between imaging obtained on the day of treatment compared to historical or referral imaging. MATERIALS AND METHODS: A retrospective cohort study was performed, evaluating all the patients presenting with eligible referral imaging in a 13-month period and comparing this imaging to the imaging taken on the day of treatment. Numbers of additional metastases, volumes and volume differences among the images were compared. RESULTS: There was a median interval of 19 days between the acquisition of the diagnostic or referral scan and the day of treatment imaging. Even the group that had the shortest interval (up to 2 weeks) showed at least one additional deposit in 50 % of the patients. Volume was increased in 75 % of this group. Longer intervals were associated with higher increases in volume. CONCLUSION: These results demonstrate the increase in the disease burden in patients with intracranial metastatic disease, in relation to number and volume, in the interval between the referral and treatment imaging. This has significant implications for planning pathways, to ensure that metastatic deposits are not missed or undertreated.

Development of brain metastases in non-small-cell lung cancer: high-risk features.

Aim: Brain metastases (BM) are a common site of disease progression and treatment failure in non-small-cell lung cancer (NSCLC) and can be identified in up to 30-50% of patients. Although they are common, there is no standardized screening protocol for development of BM in NSCLC. Multiple clinical variables predict increased BM occurrence, and, when present, should be used to initiate screening MRI.Materials & methods: We performed a single center retrospective review of NSCLC patients, examining BM development and overall survival. Available clinical, radiographic and molecular data were reviewed for association with BM and overall survival. A predictive model for BM development was created for multivariate analysis.Results: Risk factors for new BM development in NSCLC included younger age, larger primary lung tumor, Karnofsky performance score (KPS) <70, pre-existing liver or bone metastases, large cell histology and family history of cancer. Factors associated with decreased OS were larger primary lung tumor, extracranial metastases at time of diagnosis, large cell histology and poorly-differentiated carcinoma histology.Conclusion: There are multiple high risk features for developing BM in NSCLC. Each of these factors should routinely be investigated, and presence should prompt brain MRI to allow earlier diagnosis and treatment of BM.

non-small-cell lung cancer has a high rate of cancer spread and brain metastases (cancer spread to the brain). There is currently no standardized protocol for when to obtain imaging of the brain to inspect for metastases. Our study reviewed over 1000 patients with non-small-cell lung cancer to determine which factors predisposed to development of brain metastases, and which factors impacted survival. Risk factors for development of brain metastases included younger age, larger primary lung tumor, poor functional status, liver or bone metastases, large cell histology and family cancer history. Lung cancer patients with any of these risk factors should be screened for brain metastases. Factors associated with decreased overall survival were larger primary lung tumor, extracranial metastases at time of diagnosis, large cell histology and poorly-differentiated carcinoma histology.

Personalized selection of unequal sub-arc collimator angles in VMAT for multiple brain metastases.

PURPOSE: Investigating the effects of unequal sub-arc personalized collimator angle selection on the quality of Volumetric Modulated Arc Therapy (VMAT) plans for treating multiple brain metastases. METHODS: This study included 21 patients, each with 2-4 target volumes of multiple brain metastases. Two stereotactic radiotherapy (SRT) approaches were utilized: sub-arc collimator VMAT (SAC-VMAT) and fixed collimator VMAT (FC-VMAT). In the SAC-VMAT group, multi-leaf collimators (MLC) shaped the target area, dividing the full arc into four unequal sub-arcs under the beam's eye view (BEV). Each sub-arc had an appropriate collimator angle selected to mitigate 'island blocking problems'. Conversely, the FC-VMAT group used a fixed collimator angle of 15° or 345°. A comparative analysis of the dosimetric parameters of the target volumes and normal tissues, along with the monitor units (MU), was conducted between the two groups. RESULTS: The mean dose and dose-volume to normal brain tissue (2-26 Gy, with a step of 2 Gy) were significantly lower in the SAC-VMAT group (P < 0.01). There was no statistical difference between the two groups in dose to the target volumes, conformity index (CI), homogeneity index (HI), and other normal tissues (P > 0.05). Compared with the FA-VMAT group, the SAC-VMAT group significantly reduced the gradient index (GI) (4.5 ± 0.59 vs 5.2 ± 0.75, P < 0.001) and MU (1774.33 ± 181.77 vs 2001.0 ± 344.86, P < 0.001). Notably, with an increase in the number of PTV, the SAC-VMAT group demonstrated more significant improvements in the dose-volume of normal brain tissue, GI, and MU. CONCLUSIONS: In this study, personalized selection of the unequal sub-arc collimator angle ensured the prescribed dose to the PTV, CI, and HI, while significantly reducing the GI, MU, and the dose to normal brain tissue in the VMAT plan for multi-target brain metastases in the cohort of cases with 2-4 target volumes. Particularly as the number of targets increase, the advantages of this method become more pronounced.

Mitigating radiation-induced cognitive toxicity in brain metastases: More questions than answers.

The emergence of advanced systemic therapies added to the use of cranial radiation techniques has significantly improved outcomes for cancer patients with multiple brain metastases (BM), leading to a considerable increase in long-term survivors. In this context, the rise of radiation-induced cognitive toxicity (RICT) has become increasingly relevant. In this critical narrative review, we address the controversies arising from clinical trials aimed at mitigating RICT. We thoroughly examine interventions such as memantine, hippocampal avoidance irradiation during BM treatment or in a prophylactic setting, and the assessment of cognitive safety in stereotactic radiosurgery (SRS). Our focus extends to recent neuroscience research findings, emphasizing the importance of preserving not only the hippocampal cortex but also other cortical regions involved in neural dynamic networks and their intricate role in encoding new memories. Despite treatment advancements, effectively managing patients with multiple BM and determining the optimal timing and integration of radiation and systemic treatments remain areas requiring further elucidation. Future trials are required to delineate optimal indications and ensure SRS safety. Additionally, the impact of new systemic therapies and the potential effects of delaying irradiation on cognitive functioning also need to be addressed. Inclusive trial designs, encompassing patients with multiple BM and accounting for diverse treatment scenarios, are essential for advancing effective strategies in managing RICT and the treatment of BM patients.