Treatment Of Brain Metastases Research Articles

Abstract 1455: In vitro blood brain barrier model for evaluation of brain metastasis

Abstract Introduction: Brain metastasis significantly reduces the patient's quality of life and survival, but there are only a few choices of treatment for brain metastasis. The research for brain metastasis is difficult because of its complex and unique microenvironment, including blood-brain barrier (BBB). The BBB maintains strong cell adhesion of the vascular endothelial cells (ECs) to protect the brain parenchyma. The BBB is composed of three cell types: vascular endothelial cells, pericytes, and astrocytes. As the role of pericytes in maintaining the BBB function has become more evident, the reconstituted models of the BBB in which ECs, pericytes, and astrocytes are seeded on the front and back of the insert membrane have gotten our attention. In the field of cancer, the role of not only ECs but also wall cells, corresponding to pericytes in the brain, has been focused on. In this study, we aimed to create the in vitro BBB models and elucidate the interaction of the BBB and the metastasizing cancer cells. Methods: We applied a reconstituted model of the BBB consisting of ECs, pericytes, and astrocytes of human immortalized cells (Ito R, et al. Mol Pharm 2019) and created the co-culture system for evaluating brain metastasis. We constructed four co-culture systems and compared the migration ability of MDA231 in those models: EPA model (ECs, pericytes, and astrocytes), E0A model (ECs and astrocytes), EP0 model (ECs and pericytes), and E00 model (ECs only). We also analyzed the migration ability of the pairs of parental and brain metastatic (BrM) cell lines. Results: The BBB reconstituted model (EPA model), in which ECs were co-cultured with pericytes and astrocytes, showed higher trans-epithelial electrical resistance and lower permeability than the other co-culture models. When cancer cells were seeded, the EPA model strongly inhibited metastatic invasion of cancer cells compared to the other models. It suggests that both pericytes and astrocytes are essential for regulating cancer cell invasion. In addition, when the BrM cells of MDA231 and Ex3LL were seeded, the BrM cells invaded the EPA model more easily than the parental cells. It indicates that this model can reproduce in vivo brain vascular functions. Conclusion: We created the BBB reconstituted model which mimics the brain vascular microenvironment. This model reproduced the in vivo BBB function to protect brain from cancer cells and evaluated the brain metastatic ability of the cancer cells. Using this model, we showed that pericytes and astrocytes were essential for the BBB barrier function against the cancer cells. We need further investigation to elucidate the mechanism of brain metastasis using this BBB model. Citation Format: Shoko Noda-Narita, Atsu Aiba. In vitro blood brain barrier model for evaluation of brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1455.

Abstract 2817: Establishment of KRAS G12C mutant brain metastasis models for pre-clinical evaluation of KRAS G12C targeted anticancer therapy

Abstract KRAS is one of the most frequently mutated oncogenes in cancers, especially in lung cancer. Clinical research has shown that about 14% of non-small-cell lung cancers (NSCLCs) carry the KRASG12C mutation, and brain metastases are a relatively common occurrence in KRASG12C-mutated NSCLC. Approximately 30% of patients with KRASG12C mutations develop brain metastases, and those with KRAS-mutated NSCLC and untreated brain metastases have limited treatment options and poor clinical outcomes. AMG510 (Sotorasib) is a small molecule inhibitor of KRASG12C that specifically binds to inactive GDP-bound KRASG12C, preventing its oncogenic signaling. It has been approved for NSCLC by the FDA. Recent clinical studies have shown that Sotorasib exhibits some activity against KRASG12C NSCLC brain metastasis. To evaluate the in vivo activity of AMG510 for NSCLC brain metastasis treatment and provide insights for the preclinical development of new KRAS targeted inhibitors, we established advanced orthotopic models, including intracranial, intracarotid, and intracardiac metastatic models, using the NCI-H358-luc cell line, which harbors the KRASG12C mutation. We validated these models with AMG510 as a single agent or in combination with radiation, which is commonly used in brain tumor therapeutic strategies, to reveal the efficacy and brain concentration of AMG510 in KRASG12C brain metastasis models. Tumor growth and metastasis incidences were assessed using bioluminescence imaging (BLI). All animal studies were performed in an AAALAC accredited facility and aligned with animal welfare regulations. Our preliminary results reveal that AMG510 could penetrate the blood-brain barrier (BBB) and show therapeutic activity for KRASG12C brain metastatic tumors. These models represent powerful tools for clinically relevant assessment of the efficacy of novel KRAS G12C inhibitors and can be expanded for other KRAS mutations-associated brain metastasis or inhibitors. Citation Format: Qikuan Chen, Guilan Wang, Yingfei Yin. Establishment of KRAS G12C mutant brain metastasis models for pre-clinical evaluation of KRAS G12C targeted anticancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2817.

Single brain metastases - prognostic factors and impact of residual tumor burden on overall survival.

Brain metastases (BM) are a common and challenging issue, with their incidence on the rise due to advancements in systemic therapies and increased patient survival. Most patients present with single BM, some of them without any further extracranial metastasis (i.e., solitary BM). The significance of postoperative intracranial tumor volume in the treatment of singular and solitary BM is still debated. This study aimed to determine the impact of resection and postoperative tumor burden on overall survival (OS) in patients with single BM. Patients with surgically treated single BM between 04/2007-01/2020 were retrospectively included. Residual tumor burden (RTB) was determined by manual segmentation of early postoperative brain MRI (72 h). Survival analyses were performed using Kaplan-Meier estimates for univariate analysis and Cox regression proportional hazards model for multivariate analysis, using preoperative Karnofsky performance status scale (KPSS), age, sex, RTB, incomplete resection and singular/solitary BM as covariates. 340 patients were included, median age 64 years (54-71). 119 patients (35%) had solitary BM, 221 (65%) singular BM. Complete resection (RTB=0) was achieved in 73%, median preoperative tumor burden was 11.2 cm3 (5-25), and RTB 0 cm3 (0-0.2). Median OS of patients with singular BM was 13 months (4-33) vs 20 months (5-92) for solitary BM; p=0.062. Multivariate analysis revealed singular BM as independent risk factor for poorer OS: HR 1.840 (1.202-2.817), p=0.005. Complete vs. incomplete resection showed no significant OS difference (13 vs. 13 months, p=0.737). When focusing on solitary BM, complete resection led to a longer OS than incomplete resection (21 vs. 8 months), without statistical significance(p=0.250). Achieving RTB=0 resulted in higher OS for patients with solitary BM compared to singular BM (21 vs. 12 months, p=0.027). Patients who received postoperative radiotherapy (RT) had significantly longer OS compared to those without it (14 vs. 4 months, p<0.001), with favorable OS in those receiving stereotactic radiosurgery (SRS) (15 months (3-42), p<0.001) or hypofractionated stereotactic radiotherapy (HSRT). When complete intracranial tumor resection RTB=0 is achieved, patients with solitary BM have a favorable outcome compared to singular BM. Singular BM was confirmed as independent risk factor. There is a strong presumption that complete resection leads to an improved oncological prognosis. Patients with solitary BM tend to benefit with a favorable outcome following complete resection. Hence, surgical resection should be considered as a treatment option for patients presenting with either no or minimal extracranial disease. Furthermore, the highly favorable impact of postoperative RT on OS was demonstrated and confirmed, especially with SRS or HSRT.

Stereotactic Radiosurgery and Stereotactic Fractionated Radiotherapy in the Management of Brain Metastases.

The management of brain metastases (BM) remains an important and complex issue in the treatment of cancer-related neurological complications. BM are particularly common in patients diagnosed with lung, melanoma, or breast cancer. Over the past decade, therapeutic approaches for the majority of BM patients have changed. Considering and addressing the fact that patients with BM are living longer, the need to provide effective local control while preserving quality of life and neurocognition is fundamental. Over the past decade, SRS and SRT have become a more commonly chosen treatment option for BM. Despite significant advances in the treatment of BM, numerous questions remain regarding patient selection and optimal treatment sequencing. Clinical trials are critical to advancing our understanding of BM, especially as more therapeutic alternatives become available. Therefore, it is imperative for interdisciplinary teams to improve their understanding of the latest advances in SRS-SRT. This review aims to comprehensively explore SRS and SRT as treatments for BM, covering clinical considerations in their application (e.g., patient selection and eligibility), managing limited and multiple intact BM, addressing brainstem metastases, exploring combination therapies with systemic treatments, and considering the health economic perspective.

Abstract B004: Clinico-genomic characteristics of breast cancer brain metastasis: A multi-institutional analysis from AACR Project GENIE BPC

Abstract Purpose: The presence of Her2 amplification is associated with an increased risk of developing brain metastases. Brain metastases in breast cancer can be particularly challenging and have significant implications for prognosis and treatment. Common Her2-targeted therapies and small tyrosine kinase inhibitors have demonstrated the ability to penetrate the blood brain barrier and be effective in treating brain metastases. We investigated the clinico-genomic characteristics and the prognosis of brain metastasis in patients with breast cancer. Experimental design: Patients with breast cancer whose tumors underwent targeted sequencing from 2013-2018 at age 56 years old or younger at three institutions from the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (AACR Project GENIE BPC) registry were selected for data curation. The PRISSMM data model was used for real world outcomes including overall survival. We analyzed clinical and genomic characteristics, treatment, and clinical outcome data among patients with and without brain metastases, stratified by Her2 amplification and hormone-receptor status (Her2+ vs. Her2-/HR+ vs. triple-negative breast cancer (TNBC)). We explored the top 20 most frequently altered genes that were included on at least 20% of sequencing panels. Results: A total of 1019 patients with breast cancer along with their receptor subtype information were included in the study (110 patients were excluded due to either post- mortem sequencing or unknown receptor subtype). Among them, 336 (33%) patients were identified to have developed brain metastasis (n=87 with Her2+; n=181 with Her2-/HR+; and n=68 with TNBC). At time of advanced disease, the brain was the first and only distant site of disease in 41/336 (12%) and detected with extracranial sites of disease in 22/336 (7%) patients. For patients presenting with stage I-III breast cancer, the cumulative incidence of brain metastasis at 5 years from breast cancer diagnosis was higher in those with TNBC (35%; 95% CI: 25, 50) as compared to 24% (95% CI: 16, 37) and 21% (95% CI: 15, 29) for those with Her2+ and Her2-/HR+ subtypes, respectively. Median overall survival from brain metastasis was significantly longer (log-rank p&amp;lt;0.001) for those with Her2+ disease (19m, 95% CI: 13, 36) compared to those with Her2-/HR+ (8.9m, 95% CI: 6.3, 15) or TNBC (7.4m, 95% CI: 4.6, 11). Among patients who ever developed brain metastases, IKZF3 alterations occurred in 71% (20/28) of Her2+ patients but did not occur in either Her2- subtype. Additionally, frequencies of CDK12, MYC, and PTEN alterations differed across subtypes. Conclusions: Brain involvement at metastatic presentation conferred a higher risk of death than brain-sparing metastases. Triple negative and Her2+ histologies were associated with higher risk of brain involvement at metastasis presentation. Further exploration by treatment received across receptor subtypes and genomic alterations will be presented. Citation Format: Samantha Brown, Hannah E. Fuchs, Jessica A. Lavery, Katherine S. Panageas, Nelson S. Moss. Clinico-genomic characteristics of breast cancer brain metastasis: A multi-institutional analysis from AACR Project GENIE BPC [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B004.

Focused ultrasound and microbubble induced changes in the phenotype of breast cancer cell lines

Up to 10%–15% of patients with breast cancer (BC), particularly those with triple negative (TNBC) and HER2 positive subtypes, develop brain metastases. Despite aggressive treatment, the median survival for patients is 15 months. Treatment of brain metastases is challenging due to the blood–brain barrier (BBB) that limits the passage of molecules commonly used to treat primary BC into the brain parenchyma. Focused Ultrasound (FUS) and Microbubble (MB) are a non-invasive, image-guided therapeutic modality that can create a reversible, safe, and transient opening of the BBB. While this burgeoning area of research has progressed to clinical trials, the direct effects of FUS + MBs in the absence of therapeutic agents on tumor cells are poorly characterized. Therefore, this study aims to identify the FUS+MB induced changes in migration, invasion, and proliferation of representative brain-derived (BD) BC cell lines, namely, BD-MDA-MB-231 and BD-SKBR3 post-sonication in comparison to untreated cells. Results from these experiments will help guide future in-vivo studies evaluating the impact of FUS+MB on brain metastases to better understand its therapeutic implications and applications for patients.

Intracranial Efficacy of Pyrotinib and Capecitabine Combination Therapy in HER2-Positive Breast Cancer with Brain Metastases.

Approximately 50% of patients diagnosed with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (BC) are estimated to develop brain metastases (BMs). This study was aimed to assess the intracranial efficacy and survival benefits of pyrotinib and capecitabine combination therapy in the treatment of BMs in patients with HER2-positive BC. A total of 56 HER2-positive BC patients with BMs were treated with 400 mg pyrotinib once daily along with 1000 mg/m2 capecitabine twice daily for 14 days in 21-day cycles. The patients were allocated into three cohorts: (1) Cohort A composed of patients with newly diagnosed BMs without prior local radiotherapy, (2) Cohort B included patients with stable post-local radiotherapy, and (3) Cohort C composed of patients with progression following local radiotherapy. The primary endpoint was the intracranial objective response rate (CNS-ORR), while secondary endpoints included intracranial disease control rate (CNS-DCR), progression-free survival (PFS), overall survival (OS), safety, as well as QoL. The observed CNS-ORR CNS-ORR of 72.73% (95% CI 51.85-86.85%) in cohort A, 55% (95% CI 34.21-74.18%) in cohort B, and 42.86% (95% CI 21.38-67.41%) in cohort C. The mPFS was 11 months, 8.4 months, and 5.2 months in cohorts A, B, and C, respectively. Diarrhea, accounting for 23.21% of all the patients, was the most common grade 3/4 adverse event related with treatments (6/22 [27.3%] in cohort A, 4/20 [20.0%] in cohort B, and 3/14 [21.4%] in cohort C). However, there were no deaths related with treatments observed. Importantly, the QoL was efficiently maintained throughout the treatment duration. Pyrotinib and capecitabine combination therapy proved significant effectiveness as well as tolerability in treating HER2-positive BC with BMs, yielding satisfactory results, especially in radiotherapy-naive population.

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.

Converging survival trends in non-small cell lung cancer patients with and without brain metastasis receiving state-of-the-art treatment

IntroductionHistorically, patients with brain metastasis (BM) have been excluded from clinical trials investigating treatments for non-small cell lung cancer (NSCLC) due to their unfavorable prognosis. Advanced treatments have increased survival prospects for NSCLC patients with BM. This study evaluated the life expectancy of NSCLC patients with and without BM in the context of contemporary treatments.MethodsOutcome data were collected for patients with advanced NSCLC attending a tertiary medical center between 2015 and 2020. Patients were stratified according to BM status and compared for overall survival (OS) using log-rank and Cox regression analyses.ResultsThe cohort included 360 patients with NSCLC of whom 134 (37.2%) had BM. Most (95%) of cases of BM developed within the first two years: 63% at diagnosis, 18% during the first year, 14% during the second year. There was no significant difference in OS between patients without BM and those with BM (median 23.7 vs. 22.3 months, HR = 0.97, p = 0.82); patients with BM and a targetable or non-targetable mutation (40.2 vs. 31.4 months, HR = 0.93, p = 0.84, and 20.7 vs. 19.87 months, HR = 0.95, p = 0.75, respectively); and patients with symptomatic BM (23.7 vs. 19.8 months, HR = 0.95, p = 0.78). Treatment for BM (95% of patients) consisted of stereotactic radiosurgery or tyrosine kinase inhibitors, with corresponding intracranial control rates of 90% and 86%.ConclusionThe results imply that the presence of BM has no impact on the prognosis of NSCLC. The practice of excluding NSCLC patients with BM from clinical trials warrants reconsideration.

Cost of Treatment for Brain Metastases Using Data From a National Health Insurance Provider

In the United States, brain metastases (BMs) affect 10% to 20% of patients with cancer, presenting a significant health care challenge and necessitating intricate, high-cost treatments. Few studies have explored the comprehensive care cost for BMs, and none have used real insurance claims data. Partnering with a northeastern health care insurer, we investigated the true costs of various brain-directed radiation methods, aiming to shed light on treatment expenses, modalities, and their efficacy. We analyzed medical claims from Highmark Health-insured patients in Pennsylvania, Delware, West Virginia, and New York diagnosed with BMs (ICD-10 code C79.31) and treated with radiation from January 1, 2020 to July 1, 2022. Costs for radiation techniques were grouped by specific current procedural terminology claim codes. We subdivided costs into technical and physician components and separated hospital from freestanding costs for some modalities. From January 1, 2020 to July 1, 2022, 1048 Highmark Health members underwent treatment for BMs. Females (n = 592) significantly outnumbered males (n = 456), with an average age of 64.4 years. Each member had, on average, 5.309 claims costing $2015 per claim. Total cost totaled $10,697,749. Per-treatment analysis showed that hippocampal avoidance intensity modulated radiation therapy was the costliest treatment at $47,748, followed by stereotactic radiation therapy at $37,230, linear accelerator stereotactic radiosurgery (SRS) at $30,737, Gamma Knife SRS at $30,711, and whole-brain radiation therapy at $5225. Whole-brain radiation therapy was the least costly radiation technique. Similar per-treatment prices for Gamma Knife and linear accelerator SRS support their use in treating BMs. Stereotactic radiation therapy in general was costlier on a per-use basis than SRS, prompting further scrutiny on its frequent use. Hippocampal avoidance intensity modulated radiation therapy was the costliest radiation therapy on a per-use basis by a moderate amount, prompting further discussion about its comparative cost effectiveness against other radiation modalities. This study underscores the importance of multiple considerations in treating BMs, such as tumor control, survival, side effects, and costs.

Hippocampal sparing in whole-brain radiotherapy for brain metastases: controversy, technology and the future.

Whole-brain radiotherapy (WBRT) plays an irreplaceable role in the treatment of brain metastases (BMs), but cognitive decline after WBRT seriously affects patients' quality of life. The development of cognitive dysfunction is closely related to hippocampal injury, but standardized criteria for predicting hippocampal injury and dose limits for hippocampal protection have not yet been developed. This review systematically reviews the clinical efficacy of hippocampal avoidance - WBRT (HA-WBRT), the controversy over dose limits, common methods and characteristics of hippocampal imaging and segmentation, differences in hippocampal protection by common radiotherapy (RT) techniques, and the application of artificial intelligence (AI) and radiomic techniques for hippocampal protection. In the future, the application of new techniques and methods can improve the consistency of hippocampal dose limit determination and the prediction of the occurrence of cognitive dysfunction in WBRT patients, avoiding the occurrence of cognitive dysfunction in patients and thus benefiting more patients with BMs.

Interrogation of endothelial and mural cells in brain metastasis reveals key immune-regulatory mechanisms

Brain metastasis (BrM) is a common malignancy, predominantly originating from lung, melanoma, and breast cancers. The vasculature is a key component of the BrM tumor microenvironment with critical roles in regulating metastatic seeding and progression. However, the heterogeneity of the major BrM vascular components, namely endothelial and mural cells, is still poorly understood. We perform single-cell and bulk RNA-sequencing of sorted vascular cell types and detect multiple subtypes enriched specifically in BrM compared to non-tumor brain, including previously unrecognized immune regulatory subtypes. We integrate the human data with mouse models, creating a platform to interrogate vascular targets for the treatment of BrM. We find that the CD276 immune checkpoint molecule is significantly upregulated in the BrM vasculature, and anti-CD276 blocking antibodies prolonged survival in preclinical trials. This study provides important insights into the complex interactions between the vasculature, immune cells, and cancer cells, with translational relevance for designing therapeutic interventions.

Development of RLK-Unet: a clinically favorable deep learning algorithm for brain metastasis detection and treatment response assessment.

Previous deep learning (DL) algorithms for brain metastasis (BM) detection and segmentation have not been commonly used in clinics because they produce false-positive findings, require multiple sequences, and do not reflect physiological properties such as necrosis. The aim of this study was to develop a more clinically favorable DL algorithm (RLK-Unet) using a single sequence reflecting necrosis and apply it to automated treatment response assessment. A total of 128 patients with 1339 BMs, who underwent BM magnetic resonance imaging using the contrast-enhanced 3D T1 weighted (T1WI) turbo spin-echo black blood sequence, were included in the development of the DL algorithm. Fifty-eight patients with 629 BMs were assessed for treatment response. The detection sensitivity, precision, Dice similarity coefficient (DSC), and agreement of treatment response assessments between neuroradiologists and RLK-Unet were assessed. RLK-Unet demonstrated a sensitivity of 86.9% and a precision of 79.6% for BMs and had a DSC of 0.663. Segmentation performance was better in the subgroup with larger BMs (DSC, 0.843). The agreement in the response assessment for BMs between the radiologists and RLK-Unet was excellent (intraclass correlation, 0.84). RLK-Unet yielded accurate detection and segmentation of BM and could assist clinicians in treatment response assessment.

Multicentric Assessment of Safety and Efficacy of Combinatorial Adjuvant Brain Metastasis Treatment by Intraoperative Radiation Therapy and Immunotherapy

PurposeFollowing surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy (EBRT) by enabling superior organ at risk preservation, reduction of in-hospital times and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs). MethodsIn a multicentric approach incorporating individual patient data from six international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis (RN), leptomeningeal spread (LMS), local control (LC), distant brain progression (DBP) and estimated overall survival (OS). ResultsA total of 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow up was 13.2 (1.2-102.4) months and the median IORT dose was 25 (18-30) Gy prescribed to the applicator surface. There was one grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative RN rate was observed. The 1-year LCR was 98.0% and the 1-year DBP-free rate 60.0%. Median time to DBP was 5.5 (1.0-18.5) months in the subgroup of patients experiencing DBP and the cumulative LMS rate was 4.9%. The median estimated OS was 26 (1.2-not reached) months with a 1-year survival rate of 74.0%. Early initiation of IT/TT was associated with a non-significant trend towards improved DBP rate and OS. ConclusionThe combination of ICIs/TT with IORT for resected BMs does not seem to increase toxicity, while yielding encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial.

Brain Metastasis in Triple‐Negative Breast Cancer

Background. Breast cancer is an important cause of cancer‐related death in women worldwide and represents the second most frequent cause of brain metastases after lung cancer. The aim of this study was to determine the characteristics and outcomes of triple‐negative breast cancer (TNBC) patients with brain metastasis (BM). Methods. We retrospectively reviewed a cohort of patients diagnosed with TNBC at the “Instituto Nacional de Enfermedades Neoplasicas” (period 2000–2014) to evaluate patients who developed BM. Survival rates were assessed by the Kaplan–Meier method, and prognostic factors were identified with the Cox regression analysis. Results. Of a total of 2007 TNBC patients, 193 (9.62%) developed BM. Of these, 169 stages I–III patients with a median age of 45 years (range:21–78) were included. The stage in this cohort was 4 (2.4%) clinical stage (CS) I, 23 (13.6%) with CS II and 142 (84.0%) with CS III. Most of these patients presented ECOG ≥2 (68.6%). The most common symptom was headache (74.0%), followed by nausea‐vomiting (46.7%). Imaging showed that 80 patients (53.0%) had ≥1 metastatic brain lesion. Regarding the treatment of BM in this cohort, 132 patients (84.6%) received radiotherapy (RT), 2 (1.5%) surgery, and 6 (4.5%) surgery plus RT. The overall survival (OS) rate of BM was 59.8%, 37.3%, and 15.0% at 3, 6, and 12 months, respectively. A multivariate analysis showed RT to be the only factor with a positive impact on the OS of BM (hazard ratio (HR) = 0.48, 95% confidence interval (CI):0.30‐0.77, and p = 0.002), while ECOG ≥2 was associated with a worse OS (HR = 1.69, 95%CI:1.15–2.48, and p = 0.007). Conclusion. Despite the poor prognosis of TNBC patients who develop BM, RT showed a benefit in OS rates, while ECOG ≥2 was the only prognostic factor associated with a worse OS. These results may be useful for multidisciplinary teams for treatment planning in patients with TNBC and BM.

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 ina 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.

Coordination of anti-CTLA-4 with whole-brain radiation therapy decreases tumor burden during treatment in a novel syngeneic model of lung cancer brain metastasis

Lung cancer is the most common primary tumor to metastasize to the brain. Although advances in lung cancer therapy have increased rates of survival over the past few decades, control and treatment of lung cancer brain metastasis remains an urgent clinical need. Herein, we examine the temporal coordination of α-CTLA-4 administration in combination with whole-brain radiation therapy in a syngeneic preclinical model of lung cancer brain metastasis in both C57Bl/6 and athymic nude mice. Brain tumor burden, survival, and weight loss were monitored. Immunotherapy administration 24 h prior to irradiation resulted in increased brain tumor burden, while administration of immunotherapy 12 h after radiation decreased tumor burden. Neither of the treatments affected survival outcomes or weight loss due to brain tumor recurrence. These findings suggest that the coordination of α-CTLA-4 administration in addition to whole-brain radiation therapy may be a viable strategy for reduction of tumor burden for the management of lung cancer brain metastasis.

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

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

Radiotherapy in Preclinical Models of Brain Metastases: A Review and Recommendations for Future Studies.

Brain metastases (BMs) frequently occur in primary tumors such as lung cancer, breast cancer, and melanoma, and are associated with notably short natural survival. In addition to surgical interventions, chemotherapy, targeted therapy, and immunotherapy, radiotherapy (RT) is a crucial treatment for BM and encompasses whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS). Validating the efficacy and safety of treatment regimens through preclinical models is imperative for successful translation to clinical application. This not only advances fundamental research but also forms the theoretical foundation for clinical study. This review, grounded in animal models of brain metastases (AM-BM), explores the theoretical underpinnings and practical applications of radiotherapy in combination with chemotherapy, targeted therapy, immunotherapy, and emerging technologies such as nanomaterials and oxygen-containing microbubbles. Initially, we provided a concise overview of the establishment of AM-BMs. Subsequently, we summarize key RT parameters (RT mode, dose, fraction, dose rate) and their corresponding effects in AM-BMs. Finally, we present a comprehensive analysis of the current research status and future directions for combination therapy based on RT. In summary, there is presently no standardized regimen for AM-BM treatment involving RT. Further research is essential to deepen our understanding of the relationships between various parameters and their respective effects.

Whole-brain radiotherapy with hippocampus sparing and simultaneous integrated boost to metastases: A plan quality comparison study between Ethos, HyperArc, VMAT and Tomotherapy

This study provides a concise and structured overview of a dosimetric comparison study conducted to assess the feasibility and effectiveness of 4 advanced radiotherapy techniques in treating brain metastases with hippocampus sparing and simultaneous integrated boost (HS-WBRT+SIB). Eleven patients with brain metastases previously treated with radiotherapy were included in the study. Planning CT scans with 2 mm slice thickness and MR imaging were used for contouring and dose prescription. The bilateral hippocampus and other organs at risk (OARs) were automatically contoured, and hippocampal avoidance regions (HAR) were defined as a 7 mm 3D expansion around the hippocampus. Gross tumor volume for each metastasis (GTVmet) and planning target volume for metastases (PTVmet) were delineated. The whole-brain CTV (CTVWB) and planning target volume for whole brain (PTVWB) were defined accordingly. Treatment planning and optimization were conducted using state-of-the-art radiotherapy techniques: Ethos, HyperArc, VMAT, and Tomotherapy. Tomotherapy achieved the highest D98% for PTVmet, indicating the best metastasis coverage. HyperArc plans showed the highest D98% for PTVWB, suggesting superior whole-brain coverage. Tomotherapy demonstrated significantly lower D98%, D2%, and Dmean values for the hippocampus, indicating its superiority in sparing the hippocampus. VMAT resulted in the lowest D2% values for the eyes, optic nerves, brainstem, and hypophysis, showing the best sparing of these critical structures. Tomotherapy consistently achieved lower Dmean values for parotids, oral cavity, and lips compared to the other techniques. The dosimetric comparison revealed distinct strengths and weaknesses for each radiotherapy technique. Tomotherapy excelled in sparing the hippocampus, while VMAT showed promise in sparing OARs. HyperArc plans demonstrated the best overall whole-brain coverage. These findings should guide clinicians in selecting the most suitable technique based on patient characteristics and institutional resources.