Distant Brain Metastases Research Articles

Impact of Lymphatic and Venous Invasion Patterns on Postoperative Prognosis and Distant Metastasis in Esophageal Squamous Cell Carcinoma After Preoperative Chemotherapy.

Lymphovascular invasion (LVI) is reported to correlate with postoperative prognosis in esophageal squamous cell carcinoma (ESCC). However, reports analyzing lymphatic and venous invasion separately are rare, and no studies have examined the correlation in resected specimens after neoadjuvant chemotherapy (NAC). This study evaluated the postoperative prognosis and distant metastatic recurrence patterns in ESCC patients who underwent esophagectomy after NAC. This retrospective study analyzed 427 ESCC patients who underwent radical esophagectomy after NAC. The study examined the association of LVI patterns with postoperative overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS). The study also evaluated the correlation with postoperative distant metastasis patterns. Multivariate analyses showed that patients with venous invasion (VI) alone had significantly worse OS (HR, 2.99; p < 0.001), RFS (HR, 2.92; p < 0.001), and DMFS (HR, 3.63; p < 0.001) than patients without LVI. Patients with both lymphatic invasion (LI) and VI had the worst OS (HR, 4.23; p < 0.001), RFS (HR, 3.38; p < 0.001), and DMFS (HR, 4.59; p < 0.001) among all groups. For the ypN0 patients, VI positivity was the only independent risk factor for DMFS (HR, 5.33; p < 0.001). Regarding distant organ metastasis, liver, brain, and bone metastasis were more frequently detected in patients with both LI and VI than in patients with other LVI patterns. The study showed that ESCC patients treated with NAC who have resected specimens positive for VI, especially those also with positive lymphatic invasion, have a worse postoperative prognosis and a higher risk for postoperative distant metastases than those without LVI. More aggressive postoperative adjuvant therapy may be suitable for improving the prognosis of such patients.

Comprehensive analysis of stereotactic Radiosurgery outcomes in triple-negative breast cancer patients with brain metastases: The influence of immunotherapy and prognostic factors

IntroductionBreast cancer stands as the second most common solid tumors with a propensity for brain metastasis. Among metastatic breast cancer cases, the brain metastasis incidence ranges from 10 % to 30 %, with triple-negative breast cancer (TNBC) displaying a heightened risk and poorer prognosis. SRS has emerged as an effective local treatment modality for brain metastases; however, data on its outcomes specifically in pure triple-negative subtype remain scarce. MethodWe retrospectively reviewed the electronic medical records of all brain metastasis (BM) TNBC patients treated with SRS. Patient, tumour characteristics and treatment details data were collected. This retrospective cohort study aimed to evaluate local control (LC), distant brain metastasis free survival (DBMFS), and overall survival (OS) outcomes in TNBC patients undergoing SRS for brain metastases while identifying potential prognostic factors. ResultForty-three patients with TNBC and brain metastases treated with SRS between January 2017 and 2023 were included. The study found rates of LC (99 % at 1 year) and DBMFS (76 % at 1 year) after SRS, with brain metastasis count (p = 0,003) and systemic treatment modality (p = 0,001) being significant predictors of DBMFS. The median OS following SRS was 19.5 months, with neurological deficit (p = 0.003) and systemic treatment modality (p = 0.019) identified as significant predictors of OS. ConclusionSRS demonstrates favourable outcomes in terms of local control and distant brain metastasis-free survival in TNBC. Neurological deficit and systemic treatment significantly influence overall survival, emphasizing the importance of personalized treatment approaches and (magnetic resonance imaging) MRI surveillance based on these factors.

Pretreatment Spatially Aware Magnetic Resonance Imaging Radiomics Can Predict Distant Brain Metastases (DBMs) After Stereotactic Radiosurgery/Radiation Therapy (SRS/SRT)

PurposeStereotactic radiosurgery/radiotherapy (SRS/SRT) has increasingly been used to treat brain metastases. However, the development of distant brain metastases (DBMs) in the untreated brain remains a serious complication. We sought to develop a spatially aware radiomic signature to model the time-to-DBM development in a cohort of patients leveraging pre-treatment magnetic resonance imaging (MRI) and radiotherapy treatment planning data including radiation dose distribution maps. Methods and MaterialsWe retrospectively analyzed a cohort of 105 patients with brain metastases treated by SRS/SRT with pre-treatment multi-parametric MRI (T1, T1 post-contrast, T2, FLAIR). 3D radiomic features were extracted from each MRI sequence within 5 isodose regions of interest (ROIs) identified via radiation dose distribution maps and gross target volume (GTV) contours. Clinical features including patient performance status, number of lesions treated, tumor volume, and tumor stage were collected to serve as a baseline for comparison. Cox proportional hazards (CPH) modelling and Kaplan Meier analysis were used to model time-to-DBM development. ResultsCPH models trained using radiomic features achieved a mean concordance index (c-index) of 0.63 (std=0.08) compared to a c-index of 0.49 (std=0.09) for CPH models trained using clinical factors. A CPH model trained using both radiomic and clinical features achieved a c-index of 0.69 (std=0.08). The identified radiomic signature was able to stratify patients into distinct risk groups with statistically significant differences (p=0.00007) in time-to-DBM development as measured by log-rank test. Clinical features were unable to do the same. Radiomic features from the peritumoral 50-75% isodose ROI and GTV region were most predictive of DBM development. ConclusionsOur results suggest that radiomic features extracted from pre-treatment MRI and multiple isodose ROIs can model time-to-DBM development in patients receiving SRS/SRT for brain metastases, outperforming clinical feature baselines. Notably, we believe we are the first to leverage SRS/SRT dose maps for ROI identification and subsequent radiomic analysis of peritumoral and untargeted brain regions using multi-parametric MRI. We observed that the peritumoral environment may be implicated in DBM development for SRS/SRT-treated brain metastases. Our preliminary results might enable the identification of patients with predisposition to DBM development and prompt subsequent changes in disease management.

Repeated Stereotactic Radiotherapy for Local Brain Metastases Failure or Distant Brain Recurrent: A Retrospective Study of 184 Patients.

The main advantages of stereotactic radiotherapy (SRT) are to delay whole-brain radiotherapy (WBRT) and to deliver ablative doses. Despite this efficacy, the risk of distant brain metastases (BM) one year after SRT ranges from 26% to 77% and 20 to 40% of patients required salvage treatment. The role and consequences of reirradiation remain unclear, particularly in terms of survival. The objective was to study overall survival (OS) and neurological death-free survival (NDFS) and to specify the prognostic factors of long-term survival. we retrospectively reviewed the data of patients treated between 2010 and 2020 with at least two courses of SRT without previous WBRT. In total, 184 patients were treated for 915 BMs with two-to-six SRT sessions. Additional SRT sessions were provided for local (5.6%) or distant (94.4%) BM recurrence. The median number of BMs treated per SRT was one with a median of four BMs in total. The mean time between the two SRT sessions was 8.9 months (95%CI 7.7-10.1) and there was no significant difference in the delay between the two sessions. The 6-, 12- and 24-month NDFS rates were 97%, 82% and 52%, respectively. The 6-, 12- and 24-month OS rates were 91%, 70% and 38%, respectively. OS was statistically related to the number of SRT sessions (HR = 0.48; p < 0.01), recursive partitioning analysis (HR = 1.84; p = 0.01), salvage WBRT (HR = 0.48; p = 0.01) and brain metastasis velocity (high: HR = 13.83; p < 0.01; intermediate: HR = 4.93; p < 0.01). Lung cancer and melanoma were associated with a lower NDFS compared to breast cancer. A low KPS, a low number of SRT sessions, synchronous extracerebral metastases, synchronous BMs, extracerebral progression at SRT1, a high BMV grade, no WBRT and local recurrence were also associated with a lower NDFS. A high KPS at SRT1 and low BMV grade are prognostic factors for better OS, regardless of the number of BM recurrence events.

Predictive Value of Pre-Treatment MRI Radiomics for Distant Brain Metastases Following Stereotactic Radiosurgery/Radiotherapy

Local intracranial therapy for brain metastases (BM) has taken on particular importance as survival among metastatic patients improves. However, the development of distant BMs (DBMs) outside the treated area remains a stubborn problem for which canonical clinical features (age, histology, ECOG PS) have limited predictive capability. In this study, we hypothesized that MRI-based "radiomic" features (sub-visual cues extracted from diagnostic images) can accurately predict the time-to-DBM development (TTDD) on a retrospectively curated dataset of patients treated with stereotactic radiosurgery/radiotherapy (SRS/SRT). We queried our treatment planning system for patients treated with brain SRS/SRT between 2014 and 2021, and curated the incidence/timing of DBMs manually. Pre-RT MRI sequences (T1 pre, T1 post, T2, and FLAIR) and planning data were obtained for each patient. MRI and CT simulations were co-registered using affine transformations, and regions of interest (ROIs) were identified based on contoured structures (GTV) and discrete isodose ranges (0-25%, 25-50%, 50-75%, 75%+). Radiomic features were extracted from these ROIs, and clinical features (ECOG PS, tumor volume, age) were recorded for baseline comparison. Features were selected using Wald test scores from univariate Cox proportional hazard (CPH) models. Multivariate CPH models were then trained to predict TTDD using combinations of selected features. Predictive capability was evaluated using concordance index (c-index) values. A radiomic risk score (RRS) was created to discriminate patients with low and high-risk for DBMs, and evaluated using a log-rank test. A total of 105 patients were selected with a median follow up of 356 days. 53 patients developed DBMs (median time 118 days). Radiomic CPH models achieved a c-index of 0.63 compared to clinical baseline of 0.49. The combination of radiomic and clinical features achieved the highest c-index of 0.69. Overall, radiomic features with and without clinical features were able to stratify patients into low and high-risk groups with statistically significant differences in TTDD development (see Table 1). Clinical features alone were not significant. The most predictive radiomic features were identified within the T1 pre-contrast MRI from the 50-75% isodose regions, followed by T2 FLAIR/GTV and T2/GTV combinations. Radiomic features from routine MR scans were more predictive of TTDD than baseline clinical features. The contribution from the 50-75% isodose region suggests importance within the peritumoral environment in addition to the tumor itself.

Stereotactic radiosurgery for distant brain metastases secondary to esthesioneuroblastoma: a single-institution series.

Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare, malignant tumor of neuroectodermal origin that arises from the olfactory neuroepithelium. In this study the authors present the first series in the literature on distant brain metastases (BMs) secondary to ENB that were treated with stereotactic radiosurgery (SRS), to evaluate the safety and effectiveness of SRS for this indication. A retrospective analysis of clinical and radiological outcomes of patients with ENB who underwent CyberKnife (CK) SRS at a single center was conducted. The clinical and radiological outcomes of patients, including progression-free survival, overall survival, and local tumor control (LTC) were reported. Between 2003 and 2022, 32 distant BMs in 8 patients were treated with CK SRS at Stanford University. The median patient age at BM diagnosis was 62 years (range 47-75 years). Among 32 lesions, 2 (6%) had previously been treated with surgery, whereas for all other lesions (30 [94%]), CK SRS was used as their primary treatment modality. The median target volume was 1.5 cm3 (range 0.09-21.54 cm3). CK SRS was delivered by a median marginal dose of 23 Gy (range 15-30 Gy) and a median of 3 fractions (range 1-5 fractions) to a median isodose line of 77% (range 70%-88%). The median biologically effective dose was 48 Gy (range 21-99.9 Gy) and the median follow-up was 30 months (range 3-95 months). The LTC at 1-, 2-, and 3-year follow-up was 86%, 65%, and 50%, respectively. The median progression-free survival and overall survival were 29 months (range 11-79 months) and 51 months (range 15-79 months), respectively. None of the patients presented adverse radiation effects. In the authors' experience, SRS provided excellent LTC without any adverse radiation effects for BMs secondary to ENB.

INTRAMET: Results of a prospective, single-arm, open-label phase II trial of intraoperative radiotherapy after resection of brain metastases.

2031 Background: Brain metastases (BM) occur in about 10-20% of all cancer patients during the course of their disease. The current standard of care for lesions that cause mass effects is neurosurgical resection followed by adjuvant radiotherapy of the resection cavity. We here report efficacy data of the INTRAMET trial (NCT03226483), which tested intraoperative radiation therapy (IORT) using a high-dose, single fraction to the tumor bed. Methods: Patients ≥18 years and Karnofsky (KPS) ≥50 with suspected BM were included. A frozen-section confirmed metastasis and technically applicable IORT were mandatory. Exclusion criteria were surgical or MRI contraindications, meningeal infiltration, or IORT Dmax doses exceeding 8 Gy at risk structures. IORT was performed after tumor resection in the operating room with a mobile low energy X-ray device emitting a spherical radiation field with a sharp dose gradient. A dose of 30Gy was prescribed to the surface of the resection cavity. The primary endpoint was cumulative local control rate (LCR). Secondary endpoints were incidence of other (distant) BM (RCR), overall survival (OS), time to the next systemic treatment and adverse event rates (AE). Results: In total, 35 of the originally 50 planned patients were recruited. After a pre-specified interim analysis, the study was prematurely halted due to good safety and outcomes profiles. 54.3% were men, the mean age was 64 (45-85) years. The mean follow-up was 25.7 (0.8-64.5) month. At the time of this report, 51.4% of patients were alive. 68.6% primary histologies corresponded to lung primaries. The LCR was 94.3% (95% CI 82.9-98.8%) and RCR was 57.1% (95% CI 40.7-72.4%,). 8.6% patients or lesions developed out of field leptomeningeal progression. The mean OS was 37.4 months (95% CI 28.9-46.9). For those patients undergoing salvage whole brain RT (WBRT), the median initiation time was 147 (20-601) days with a significant survival benefit for those not requiring WBRT (p = 0.027). No significant survival differences were identified according to primary histology (p = 0.618), immunotherapy (p = 0.928), seizures at baseline (p = 0.169), KPS (p = 0.056) or radionecrosis appearance (p = 0.214). Mean time to next systemic treatment was 45.0 (95% CI 35.1-54.8) days. No G4-5 AE related to IORT occurred. The overall radionecrosis (RN) rate was 20% (n = 5 G1, n = 1 G2, n = 1 G3). No risk factors could be associated to RN. Post-surgical seizures were present in 28.6% patients, with eloquent localizations as the only predictive factor (p = 0.008). Conclusions: IORT for resected BM yields excellent local control rates and has a toxicity profile similar to those reported in post-operative SRS trials. By easing a prompt initiation of subsequent systemic treatments, IORT might shorten the overall treatment courses of many cancer patients. Clinical trial information: NCT03226483 .

Acute toxicities and cumulative dose to the brain of repeated sessions of stereotactic radiotherapy (SRT) for brain metastases: a retrospective study of 184 patients

BackgroundStereotactic radiation therapy (SRT) is a focal treatment for brain metastases (BMs); thus, 20 to 40% of patients will require salvage treatment after an initial SRT session, either because of local or distant failure. SRT is not exempt from acute toxicity, and the acute toxicities of repeated SRT are not well known. The objective of this study was to analyze the acute toxicities of repeated courses of SRT and to determine whether repeated SRT could lead to cumulative brain doses equivalent to those of whole-brain radiotherapy (WBRT).Material and methodsBetween 2010 and 2020, data from 184 patients treated for 915 BMs via two to six SRT sessions for local or distant BM recurrence without previous or intercurrent WBRT were retrospectively reviewed. Patients were seen via consultations during SRT, and the delivered dose, the use of corticosteroid therapy and neurological symptoms were recorded and rated according to the CTCAEv4. The dosimetric characteristics of 79% of BMs were collected, and summation plans of 76.6% of BMs were created.Results36% of patients developed acute toxicity during at least one session. No grade three or four toxicity was registered, and grade one or two cephalalgy was the most frequently reported symptom. There was no significant difference in the occurrence of acute toxicity between consecutive SRT sessions. In the multivariate analysis, acute toxicity was associated with the use of corticosteroid therapy before irradiation (OR = 2.6; p = 0.01), BMV grade (high vs. low grade OR = 5.17; p = 0.02), and number of SRT sessions (3 SRT vs. 2 SRT: OR = 2.64; p = 0.01). The median volume equivalent to the WBRT dose (VWBRT) was 47.9 ml. In the multivariate analysis, the VWBRT was significantly associated with the total GTV (p < 0.001) and number of BMs (p < 0.001). Even for patients treated for more than ten cumulated BMs, the median BED to the brain was very low compared to the dose delivered during WBRT.ConclusionRepeated SRT for local or distant recurrent BM is well tolerated, without grade three or four toxicity, and does not cause more acute neurological toxicity with repeated SRT sessions. Moreover, even for patients treated for more than ten BMs, the VWBRT is low.

Stereotactic radiosurgery in brain metastasis: treatment outcomes and patterns of failure

Abstract Introduction: Stereotactic radiosurgery (SRS) has become a preferred treatment in the initial management of brain metastases (BM). This study reported treatment outcomes and identified the patient, tumour, and treatment-related factors that predict failure, survival, and brain necrosis (BN). Methods: We retrospectively reviewed the electronic medical records of all BM patients treated with SRS. Patient, tumour characteristics and treatment details data were collected. All recurrences and BN were defined in the neurooncological tumour board. Results: From December 2016 to April 2020, 148 patients were analysed. The median follow-up was 14·8 months (range 6–51). At the time of analyses, 72·3% of the patients were alive. Presence of initial neurological deficit (HR; 2·71 (1·07–6·9); p = 0·036) and prior RT (HR; 2·55 (1·28–5·09); p = 0·008) is associated with worse overall survival. The local recurrence rate was 11·5 %. The distant brain metastasis rate was 53·4 %. Leptomeningeal metastasis was seen in 11 patients (7·4%). Symptomatic BN was seen in 19 patients (12·8 %). Bigger lesions (13 versus 23 mm diameter; p = 0·034) and cavity radiosurgery are associated with more BN (63·2 % versus 36·8%; p: 0·004). Conclusions: Distant BM is the leading cause of CNS recurrences and, salvage SRS is possible. Due to the increasing risk of developing BN routine metastasectomy should be made with caution.

Treatment Outcome of Gamma Knife Radiosurgery for Brain Metastasis from Thyroid Cancer: Favorable Local Control but Poor Survival

Brain metastasis from thyroid cancer (TCBM) is extremely rare; thus, despite a good treatment outcome for thyroid cancer, TCBM has shown poor clinical outcomes. Considering the short survival and poor general condition of patients with TCBM, stereotactic radiosurgery may be preferred to achieve local control. A total of 25 patients with TCBM who underwent Gamma Knife radiosurgery (GKS) were initially included in this study; however, 3 patients were excluded because of a lack of data. There were 7 men (31.8%) and 15 women (68.2%) and the mean age was 63.7 years. The most common type of thyroid cancer histology was papillary carcinoma. Fourteen patients (63.6%) harbored single brain metastatic tumor and 8 (36.3%) had multiple brain metastatic tumors. The mean duration from thyroid cancer diagnosis to detection of brain metastasis was 7.7 years (range, 0-23 years). The median dose of radiation of GKS was 22 Gy (range, 18-25 Gy). There was no radiation-induced complication after GKS. The median overall survival (OS) was 15 months and the 1-year OS of patients with TCBM was 63%, the 2-year OS was 38%, and the 5-year OS was 28%. The 6-month progression-free survival (PFS) for local recurrence of TCBM was 90.4%, the 1-year PFS was 84%, and the 3-year PFS was 84%. GKS showed favorable local control for TCBM. However, the rate of distant brain metastasis was high and median survival of patients with TCBM was only 15 months.

Radionecrosis after repeated courses of radiotherapy under stereotactic conditions for brain metastases: Analysis of clinical and dosimetric data from a retrospective cohort of 184 patients

PurposeBetween 10 and 40% of patients with cancer will develop one or more brain metastases (BMs). Stereotactic radiotherapy (SRT) is part of the therapeutic arsenal for the treatment of de novo or recurrent BM. Its main interest is to delay whole brain radiation therapy (WBRT), which may cause cognitive toxicity. However, SRT is not exempt from long-term toxicity, and the most widely known SRT is radionecrosis (RN). The objective of this study was to analyze the occurrence of RN per BM and per patient. Material and methodsBetween 2010 and 2020, data from 184 patients treated for 915 BMs by two to six SRT sessions for local or distant brain recurrence without previous or intercurrent WBRT were retrospectively reviewed. RN was examined on trimestral follow-up MRI and potentially confirmed by surgery or nuclear medicine. For each BM and SRT session plan, summation V12Gy, V14Gy, V21Gy and V23Gy isodoses were collected. Volumes of intersections were created between the 12Gy isodose at the first SRT and the 18Gy isodose of the following SRT (V18-12Gy). ResultsAt the end of follow-up, 23.0% of patients presented RN, and 6.3% of BM presented RN. Median follow-up of BM was 13.3 months (95%CI 18.3–20.8). The median interval between BM irradiation and RN was 8.7 months (95% CI 9.2–14.7). Six-, 12- and 24-month RN-free survival rates per BM were 75%, 54% and 29%, respectively. The median RN-free survival per patient was 15.3 months (95% CI 13.6–18.1). In multivariate analysis, the occurrence of RN per BM was statistically associated with local reirradiation (P<0.001) and the number of SRTs (P<0.001). In univariate analysis, the occurrence of RN per patient was statistically associated with the sum of all V18-12Gy (P=0.02). No statistical association was found in multivariate analysis. A sum of all V18-12Gy of less than 1.5ml was associated with a 14.6% risk of RN, compared with 35.6% when the sum of all V18-12Gy was superior to 1.5ml. The sum of all V18-12Gy larger than 1.5ml was associated with a 74% specificity and 53% sensitivity of RN (P<0.001). ConclusionBased on these results, a small number of BMs show RN during repeated SRT for local or distant recurrent BMs. Local reirradiation was the most predictive factor of brain RN. A V18-12Gy larger than 7.6ml in the case of local reirradiation or larger than 1.5ml in proximity reirradiation were prognostic factors of RN. The more BM patients need radiation therapy, and the longer they survive after irradiation, the higher their individual risk of developing RN.

IMMU-03. IMMUNE CHECKPOINT INHIBITORS IN SMALL CELL LUNG CANCER PATIENTS DEVELOPING BRAIN METASTASES

Abstract INTRODUCTION Small cell lung cancer (SCLC) is known for rapid growth, and about 40-50% of SCLC patients will develop brain metastases (BM). The addition of immune checkpoint inhibitors (ICI) to the standard chemotherapy, which is the current backbone of first-line therapy, has resulted in more prolonged survival than chemotherapy alone in SCLC patients. PURPOSE This study aimed to assess the effect of ICI before BM development in SCLC patients on time to BM development and survival. METHODS A single-institutional retrospective review of SCLC patients that underwent cranial radiation therapy between January 2014 and June 2020 was performed to assess the impact of ICI therapy on time to BM development, overall survival (OS), and time to failure of BM treatment (defined as local or distant BM recurrence) using a multivariable Cox Proportional Hazards model. RESULTS Among 197 included patients, 23 patients (11.7%) received ICI before BM development. Extensive stage of SCLC at diagnosis was observed in eighteen patients (78.2%) in the ICI group and 133 (76.4%) in the non-ICI group. In total, seventeen patients (8.6%) received prophylactic cranial irradiation, of which seven patients (30.4%) also received ICI. ICI were associated with prolonged time to BM in comparison with the non-ICI group (HR = 0.29, 95% CI: 0.18-0.47). ICI were also associated with an increased OS (HR = 0.56, 95% CI: 0.32-0.97) and prolonged time to BM treatment failure (HR = 0.32, 95% CI: 0.15-0.71) in comparison with patients who did not receive ICI. CONCLUSION The use of ICI before BM development was associated with a longer time to BM. Additionally, ICI therapy was associated with an increased OS and prolonged BM treatment failure. These results are a proof of concept of the potential benefit of ICI therapy in SCLC patients, and the presented results should be further validated in larger cohorts.

Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer

Despite recent progress in therapeutic strategies, prognosis of metastatic triple-negative breast cancer (TNBC) remains dismal. Evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1s) is critical for the generation of CD8+ T cells that mediate the regression of mammary tumors and potentiate anti-PD-1/PD-L1 therapeutic efficacy. However, it remains unknown whether this strategy is effective against metastatic TNBC, which is poorly responsive to immunotherapy. Here, using a mouse model of TNBC, we established orthotopic mammary tumors and brain metastases, and treated mammary tumors with in situ immunomodulation (ISIM) consisting of intratumoral injections of Flt3L to mobilize cDC1s, local irradiation to induce immunogenic tumor cell death, and TLR3/CD40 stimulation to activate cDC1s. ISIM treatment of the mammary tumor increased circulating T cells with effector phenotypes, and infiltration of CD8+ T cells into the metastatic brain lesions, resulting in delayed progression of brain metastases and improved survival. Furthermore, although anti-PD-L1 therapy alone was ineffective against brain metastases, ISIM overcame resistance to anti-PD-L1 therapy, which rendered these tumor-bearing mice responsive to anti-PD-L1 therapy and further improved survival. Collectively, these results illustrate the therapeutic potential of multimodal intralesional therapy for patients with unresectable and metastatic TNBC.

Nivolumab and stereotactic radiosurgery for patients with breast cancer brain metastases: A non-randomized, open-label phase Ib study.

e14010 Background: There may be a potential synergy intracranially between stereotactic radiation and immune checkpoint inhibition in brain metastases management. We hypothesize treatment with nivolumab and stereotactic radiosurgery (SRS) will be feasible and well tolerated and may improve intracranial tumor control rates compared to SRS alone in the management of breast cancer brain metastases. Methods: The study was designed as a prospective, single-arm, nonrandomized, open-label, phase Ib trial of nivolumab and SRS among patients with metastatic breast cancer brain metastases. Key eligibility criteria included patients with breast cancer brain metastases of all subtypes, age ≥ 18, ECOG ≤ 2 with ≤ 10 brain metastases. The primary objective was to evaluate the safety and feasibility of study therapy. Secondary objectives included evaluation of local brain metastasis control, distant brain metastasis control, progression free survival (PFS), and overall survival following study therapy. Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) and immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria were used to assess intracranial and extracranial disease, respectively. Treatment was initiated with a dose of nivolumab (480 mg IV) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT03807765. Results: Between February 2019 and July 2020, a total of 12 patients were treated to 17 lesions. Median follow-up from start of protocol therapy is currently 9.6 months (range: 2.8-18.7 months). No dose limiting toxicities (DLTs) were noted in our patient population. The most common neurologic adverse events included grade 1-2 headaches and dizziness occurring in 5 (42%) of patients. Median intracranial control was 6.2 months (95% CI 3.0 -14) with 6 and 12 month control rates of 55% and 22%, respectively. A total of 4 patients had systemic progression during the study. Median time to systemic PFS has not been reached with 6 and 12 month rates of 63% and 51%, respectively. Conclusions: Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. Preliminary studies reveal activity in certain breast cancer patients to study therapy. Clinical trial information: NCT03807765.

Gamma Knife Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy or Targeted Therapy.

Simple SummaryIn non-small cell lung cancer patients with brain metastases, combined Gamma Knife radiosurgery and immunotherapy or targeted therapy showed an increase in overall survival. The combination of Gamma Knife radiosurgery and immunotherapy or targeted therapy did not increase complications related to radiosurgery. Therefore, the combined treatment seems to be a safe and powerful treatment option for non-small cell lung cancer patients with brain metastases.The combination of Gamma Knife radiosurgery (GKRS) and systemic immunotherapy (IT) or targeted therapy (TT) is a novel treatment method for brain metastases (BMs) in non-small cell lung cancer (NSCLC). To elucidate the safety and efficacy of concomitant IT or TT on the outcome after GKRS, 496 NSCLC patients with BMs, who were treated with GKRS were retrospectively reviewed. The median time between the initial lung cancer diagnosis and the diagnosis of brain metastases was one month. The survival after the initial BM diagnosis was significantly longer than the survival predicted by prognostic BM scores. After the first Gamma Knife radiosurgery treatment (GKRS1), the estimated median survival was 9.9 months (95% CI = 8.3–11.4). Patients with concurrent IT or TT presented with a significantly longer survival after GKRS1 than patients without IT or TT (p < 0.001). These significant differences in the survival were also apparent among the four treatment groups and remained significant after adjustment for Karnofsky performance status scale (KPS), recursive partitioning analysis (RPA) class, sex, and multiple BMs. About half of all our patients (46%) developed new distant BMs after GKRS1. Of note, no statistically significant differences in the occurrence of radiation reaction, radiation necrosis, or intralesional hemorrhage in association with IT or TT at or after GKRS1 were observed. In NSCLC-BM patients, the concomitant use of GKRS and IT or TT showed an increase in overall survival without increased complications related to GKRS. Therefore, the combined treatment with GKRS and IT or TT seems to be a safe and powerful treatment option and emphasizes the role of radiosurgery in modern BM treatment.

24. LOCAL TUMOR PROGRESSION IS A RISK FACTOR FOR POSTOPERATIVE SEIZURES IN PATIENTS WITH BRAIN METASTASIS

PURPOSEBrain tumor-related epilepsy (BTRE) occurs in 20–35% of patients with brain metastases (BM) and influences morbidity, mortality as well as quality of life. Several factors associated with seizure risk have been identified, including incomplete resection and supratentorial localization of BM. In primary brain tumors like lower grade glioma, tumor growth is associated with seizures. However, it remains to be elucidated whether this holds also true for patients with BM. METHOD: We identified 295 patients who had been diagnosed with BM between 2004 and 2014 by review of our electronic chart system. Occurrence of new onset of postoperative seizures dependent on BM progression was tested during the clinical course as well as pattern of progression and previously described predictors of postoperative seizures. Chi-square test was used for univariate analysis, a Cox-regression model for multivariate testing.RESULTSPostoperative seizures were observed in 49 of 295 patients (16.6%). Supratentorial localization (p=0.043, OR 4.45, 95% CI 1.1–19.3) and incomplete resection (p=0.018, OR 3.68, 95% CI 1.4–10.9), along with intracranial (p=0.038, OR 1.4, 95% CI 1.4–5.8) but not extracranial progression (p=0.729, OR 0.90, 95% CI 0.4–1.7) were confirmed as factors independently associated with postoperative seizures. Furthermore, there was a significantly higher rate of postoperatives seizures in patients with local progression (18 of 84 patients, 21.4 %) compared to those with distant brain progression (12 of 93 patients, 12.9%, p=0.042, Chi-square test).CONCLUSIONHere we define tumor progression as a risk factor for the development of postoperative seizures in a well defined cohort of BM patients. Extracranial tumor recurrence seems to be not significant for seizure risk. Subgroup analysis indicates that patients with local progression of BM are more prone to seizures than those with new, distant BM lesions. Patients with local tumor recurrence might thus be candidates for primary prophylaxis with antiepileptic drugs.

Prognostic value of different metastatic sites for patients with FIGO stage IVB endometrial cancer after surgery: ASEER database analysis.

This study aimed to investigate the association between different metastatic sites and survival in endometrial cancer (EC) patients with International Federation of Gynecology and Obstetrics (FIGO) stage IVB disease. FIGO stage IVB patients with EC were selected from the surveillance, epidemiology, and end resultsdatabase. Overall survival (OS) and cause-specific survival (CSS) were analyzed with Kaplan-Meier analysis and log-rank tests. Univariate and multivariate Cox proportional hazard models were used to identify the prognostic factors for OS and CSS. A total of 929 FIGO stage IVB patients with EC were identified. Patients with peritoneum metastasis were associated with significantly better OS and CSS compared to those with organ-specific metastasis (median OS: 29 vs 19 months, P = .005; median CSS: 47 vs 25 months, P < .001). Moreover, the survival superiority of peritoneum metastasis remained significant when organ-specific metastasis was further classified into specific single-organ metastasis. The multivariate analysis also indicated that compared with peritoneum metastasis, bone, brain, and lung metastasis were independent prognostic factors for worse OS. Similarly, distant lymph node, bone, brain, liver, and lung metastasis were associated with worse CSS. Metastatic sites affected prognosis in FIGO stage IVB patients with EC. Patients with peritoneum metastasis had significantly better survival outcomes than those with organ-specific metastasis.

Predicting the Risk of Subsequent Distant Brain Metastases After Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy in Elderly Patients.

Treatment for elderly patients with few brain metastases is controversial. A score was generated to predict distant brain metastases (DBMs) after stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). Ten characteristics were retrospectively analyzed for freedom from new DBMs in 104 elderly patients receiving SRS or FSRT alone for 1-3 brain metastases. Characteristics that were significant or showed a trend on multivariate analysis were used for the score. On multivariate analysis, favorable histology (p=0.026) and single brain metastasis (p=0.006) showed significant associations with freedom from DBMs. A trend was found for supra-tentorial location only (p=0.065). Three groups were designed, 10-14, 16-20 and 21-25 points, with 6-month rates of freedom from DBMs of 10%, 54% and 95%, respectively (p<0.0001). Positive predictive values to predict DBMs and freedom from DBMs at 6 months were 91% and 94%. This new score provided high accuracy in predicting DBMs and freedom from DBMs.

Stereotactic Cavity Irradiation or Whole-Brain Radiotherapy Following Brain Metastases Resection-Outcome, Prognostic Factors, and Recurrence Patterns.

Introduction: Following the resection of brain metastases (BM), whole-brain radiotherapy (WBRT) is a long-established standard of care. Its position was recently challenged by the less toxic single-session radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) of the resection cavity, reducing dose exposure of the healthy brain.Patients and Methods: We analyzed 101 patients treated with either SRS/FSRT (n = 50) or WBRT (n = 51) following BM resection over a 5-year period. Propensity score adjustment was done for age, total number of BM, timepoint of BM diagnosis, controlled primary and extracranial metastases. A Cox Proportional Hazards model with univariate and multivariate analysis was fitted for overall survival (OS), local control (LC) and distant brain control (DBC).Results: Median patient age was 61 (interquartile range, IQR: 56–67) years and the most common histology was non-small cell lung cancer, followed by breast cancer. 38% of the patients had additional unresected BM. Twenty-four patients received SRS, 26 patients received FSRT and 51 patients received WBRT. Median OS in the SRS/FSRT subgroup was not reached (IQR NA−16.7 months) vs. 12.6 months (IQR 21.3–4.4) in the WBRT subgroup (hazard ratio, HR 3.3, 95%-CI: [1.5; 7.2] p < 0.002). Twelve-months LC-probability was 94.9% (95%-CI: [88.3; 100.0]) in the SRS subgroup vs. 81.7% (95%-CI: [66.6; 100.0]) in the WBRT subgroup (HR 0.2, 95%-CI: [0.01; 0.9] p = 0.037). Twelve-months DBC-probabilities were 65.0% (95%-CI: [50.8; 83.0]) and 58.8% (95%-CI: [42.9; 80.7]), respectively (HR 1.4, 95%-CI: [0.7; 2.7] p = 0.401). In propensity score-adjusted multivariate analysis, incomplete resection negatively impacted OS (HR 3.9, 95%-CI: [2.0;7.4], p < 0.001) and LC (HR 5.4, 95%-CI: [1.3; 21.9], p = 0.018). Excellent clinical performance (HR 0.4, 95%-CI: [0.2; 0.9], p = 0.030) and better graded prognostic assessment (GPA) score (HR 0.4, 95%-CI: [0.2; 1.0], p = 0.040) were prognostic of superior OS. A higher number of BM was associated with a greater risk of developing new distant BM (HR 5.6, 95%-CI: [1.0; 30.4], p = 0.048). In subgroup analysis, larger cavity volume (HR 1.1, 95%-CI: [1.0; 1.3], p = 0.033) and incomplete resection (HR 12.0, 95%-CI: [1.2; 118.3], p = 0.033) were associated with inferior LC following SRS/FSRT.Conclusion: This is the first propensity score-adjusted direct comparison of SRS/FSRT and WBRT following the resection of BM. Patients receiving SRS/FSRT showed longer OS and LC compared to WBRT. Future analyses will address the optimal choice of safety margin, dose and fractionation for postoperative stereotactic RT of the resection cavity.

Post-operative radiation therapy to the surgical cavity with standard fractionation in patients with brain metastases

The paradigm for post-operative cavity radiation therapy has shifted to more targeted, less morbid approaches. Single-fraction or hypofractionated radiation therapy is a common approach to treating the postoperative cavity but is associated with a local failure rate 20–40%. We employed an alternative treatment strategy involving fractionated partial brain radiation therapy to the surgical cavity. Patients with brain metastases who underwent radiation treatment 30–42 Gy in 3 Gy/fraction regimens to surgical cavity were retrospectively identified. The 6-month and 12-month freedom from local failure rates were 97.0% and 88.2%. Three patients (7%) experienced local failure at 4, 6, and 22 months. Of these, the histologies were colorectal adenocarcinoma (N = 1) and breast adenocarcinoma (N = 2). The 6-month and 12-month freedom from distant brain metastases rates were 74.1% and 68.8%, respectively, and the 6-month and 12-month overall survival rates were 84.9% and 64.3% respectively. The median overall survival was 39 months, and there were no events of late radionecrosis. Fractionated partial brain irradiation to the surgical cavity of resected brain metastases results in low rates of local failure. This strategy represents an alternative to SRS and WBRT.