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Background: A reduced Karnofsky performance score (KPS) often leads to the discontinuation of surgical and adjuvant therapy, owing to a lack of evidence of survival and quality of life benefits. This study aimed to examine the clinical and treatment outcomes of patients with KPS < 70 after neurosurgical resection and identify prognostic factors associated with better survival. Methods: Patients with a preoperative KPS < 70 who underwent surgical resection for newly diagnosed brain metastases (BM) between 2007 and 2020 were retrospectively analyzed. The KPS, age, sex, tumor localization, cumulative tumor volume, number of lesions, extent of resection, prognostic assessment scores, adjuvant radiotherapy and systemic therapy, and presence of disease progression were analyzed. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with better survival. Survival > 3 months was considered favorable and ≤ 3 months as poor. Results: A total of 140 patients were identified. Median overall survival was 5.6 months (range 0-58). There was no difference in the preoperative KPS between the groups of > 3 and ≤ 3 months (50; range, 20-60 vs. 50; range, 10-60, p = 0.077). There was a significant improvement in KPS after surgery in patients with a preoperative KPS of 20% (20 vs 40 ± 20, p = 0.048). In the other groups, no significant changes in KPS were observed. Adjuvant radiotherapy was associated with better survival (44 [84.6%] vs. 32 [36.4%]; hazard ratio [HR], 0.0363; confidence interval [CI], 0.197-0.670, p = 0.00199). Adjuvant chemotherapy and immunotherapy resulted in prolonged survival (24 [46.2%] vs. 12 [13.6%]; HR 0.474, CI 0.263-0.854, p = 0.013]. Systemic disease progression was associated with poor survival (36 [50%] vs. 71 [80.7%]; HR 5.975, CI 2.610-13.677, p < 0.001]. Conclusion: Neurosurgical resection is an appropriate treatment modality for patients with low KPS. Surgery may improve functional status and facilitate further tumor-specific treatment. Combined treatment with adjuvant radiotherapy and systemic therapy was associated with improved survival in this cohort of patients. Systemic tumor progression has been identified as an independent factor for a poor prognosis. There is almost no information regarding surgical and adjuvant treatment in patients with low KPS. Our paper provides novel data on clinical outcome and survival analysis of patients with BM who underwent surgical treatment. [ABSTRACT FROM AUTHOR]

The early prediction of overall survival (OS) in patients with lung cancer brain metastases (BMs) after Gamma Knife radiosurgery (GKRS) can facilitate patient management and outcome improvement. However, the disease progression is influenced by multiple factors, such as patient characteristics and treatment strategies, and hence satisfactory performance of OS prediction remains challenging. Accordingly, we proposed a deep learning approach based on comprehensive predictors, including clinical, imaging, and genetic information, to accomplish reliable and personalized OS prediction in patients with BMs after receiving GKRS. Overall 1793 radiomic features extracted from pre-GKRS magnetic resonance images (MRI), clinical information, and epidermal growth factor receptor (EGFR) mutation status were retrospectively collected from 237 BM patients who underwent GKRS. DeepSurv, a multi-layer perceptron model, with 4 different aggregation methods of radiomics was applied to predict personalized survival curves and survival status at 3, 6, 12, and 24 months. The model combining clinical features, EGFR status, and radiomics from the largest BM showed the best prediction performance with concordance index of 0.75 and achieved areas under the curve of 0.82, 0.80, 0.84, and 0.92 for predicting survival status at 3, 6, 12, and 24 months, respectively. The DeepSurv model showed a significant improvement (p < 0.001) in concordance index compared to the validated lung cancer BM prognostic molecular markers. Furthermore, the model provided a novel estimate of the risk-of-death period for patients. The personalized survival curves generated by the DeepSurv model effectively predicted the risk-of-death period which could facilitate personalized management of patients with lung cancer BMs. [ABSTRACT FROM AUTHOR]

Metastases in the brain are the most severe and devastating complication of cancer. The incidence of brain metastasis is increasing. Therefore, the need of finding specific druggable targets for brain metastasis is demanding. The aim of this study was to compare the brain (immune) response to brain metastases of the most common tumor lineages, viz., lung adenocarcinoma and breast cancer. Targeted gene expression profiles of 11 brain metastasis of lung adenocarcinoma (BM-LUAD) were compared to 11 brain metastasis of breast cancer (BCBM) using NanoString nCounter PanCancer IO 360™ Panel. The most promising results were validated spatially using the novel GeoMx™ Digital Spatial Profiler (DSP) Technology. Additionally, Immune cell profiles and expression of drug targets were validated by multiplex immunohistochemistry. We found a more active immune response in BM-LUAD as compared to BCBM. In the BM-LUAD, 138 genes were upregulated as compared to BCBM (adj. p ≤ 0.05). Conversely, in BCBM 28 genes were upregulated (adj. p ≤ 0.05). Additionally, genes related to CD45 + cells, T cells, and cytotoxic T cells showed to be expressed higher in BM-LUAD compared to BCBM (adj. p = 0.01, adj. p = 0.023, adj. p = 0.023, respectively). The spatial quantification of the immune cells using the GeoMx DSP technique revealed the significantly higher quantification of CD14 and CD163 in tumor regions of BM-LUAD as compared to BCBM. Importantly, the immune checkpoint VISTA and IDO1 were identified as highly expressed in the BM-LUAD. Multiplex immunohistochemistry confirmed the finding and showed that VISTA is expressed mainly in BM-LUAD tumor cells, CD3 + cells, and to fewer levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumors of different lineages. We found a far more extensive infiltration of immune cells in BM-LUAD as compared to BCBM. In addition, we found higher expression of VISTA and IDO1 in BM-LUAD. Taken together, targeted immune therapy should be considered to treat patients with BM-LUAD. [ABSTRACT FROM AUTHOR]

Background: Stereotactic 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 methods: Between 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. Results: 36% 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. Conclusion: Repeated 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. [ABSTRACT FROM AUTHOR]

Background: Current evidence‐based guidelines support stereotactic radiosurgery (SRS) for patients with up to four brain metastases (BMs). However, debate continues about how many tumors may be treated by SRS alone. Methods: This retrospective study included non–small cell lung cancer (NSCLC) patients with BMs treated with gamma knife as the initial treatment for cerebral lesions. The patients were followed up to obtain their survival information. The outcomes were statistically analyzed to compare the differences in survival between the <5 BMs and ≥5 BMs groups and to identify prognostic factors. Results: A total of 77 patients were divided into two groups (54 patients with <5 BMs and 23 patients with ≥5 BMs). The median overall survival (OS) was 18.3 months in the <5 BMs group and 17.7 months in the ≥5 BMs group. The median intracranial progression‐free survival (IPFS) was 9.0 months in the <5 BMs group and 9.9 months in the ≥5 BMs group. There was no significant difference in OS and IPFS between the two groups. The multivariate analysis demonstrated that adenocarcinoma, controlled primary cancer, higher Karnofsky Performance Scale (KPS), and salvage treatment were independent prognostic factors favoring longer OS. Conclusion: SRS alone as the initial treatment for NSCLC patients with more than four BMs was non‐inferior to SRS for those with one to four BMs in terms of OS and IPFS. [ABSTRACT FROM AUTHOR]

Brain metastasis (BM) are uncommon among women with epithelial ovarian cancer (EOC). The frequency, risk factors and clinical repercussions of BM in these patients are not well described. We retrospectively evaluated EOC patients treated at our center from 2002 to 2020 and assessed their clinical parameters, risk for BM development and association with overall survival (OS). This cohort has a known high frequency of BRCA mutation carriers (BRCAm) due to women of Ashkenazi Jewish descent. Among 1035 EOC patients, 29 (2.8%) were diagnosed with BM. The prevalence of BRCA mutations was more common among women with BM (56.5% vs. 34.3%, p = 0.033). The BM rate in patients with BRCAm was higher than the BM rate in those with wildtype BRCA (BRCAw; 5.1% vs. 2.1%, OR = 2.6; 95% CI: 1.2–5.4, p = 0.013). Median time from diagnosis to BM and from disease recurrence to BM was longer among patients with BRCAm. Median OS was not significantly different among patients with BM versus those without BM (59.4 vs. 73.4 months, p = 0.243). After BM diagnosis, median OS was not statistically significantly different between patients with BRCAm and those with BRCAw (20.6 vs. 12.3 months, p = 0.441). Treatment with poly (ADP-ribose) polymerase inhibitors and bevacizumab had no impact on subsequent development of BM. BM are rare among EOC patients. However, the risk is three-fold higher among patients with BRCAm. BM do not significantly alter OS among EOC patients. The higher rate of BM in patients with BRCAm may be related to longer OS in this subpopulation. [ABSTRACT FROM AUTHOR]

Background: Stereotactic radiosurgery (SRS) is the standard treatment for limited intracranial metastases. With the advent of frameless treatment delivery, fractionated stereotactic radiotherapy (FSRT) has become more commonly implemented given superior control and toxicity rates for larger lesions. We reviewed our institutional experience of FSRT to brain metastases without size restriction. Methods: We performed a retrospective review of our institutional database of patients treated with FSRT for brain metastases. Clinical and dosimetric details were abstracted. All patients were treated in 3 or 5 fractions using LINAC-based FSRT, did not receive prior cranial radiotherapy, and had at least 6 months of MRI follow-up. Overall survival was estimated using the Kaplan–Meier method. Local failure and radionecrosis cumulative incidence rates were estimated using a competing risks model with death as the competing risk. Univariable and multivariable analyses using Fine and Gray's proportional subdistribution hazards regression model were performed to determine covariates predictive of local failure and radionecrosis. Results: We identified 60 patients and 133 brain metastases treated at our institution from 2016 to 2020. The most common histologies were lung (53%) and melanoma (25%). Most lesions were >1 cm in diameter (84.2%) and did not have previous surgical resection (88%). The median duration of imaging follow-up was 9.8 months. The median survival for the whole cohort was 20.5 months. The local failure at 12 months was 17.8% for all lesions, 22.1% for lesions >1 cm, and 13.7% for lesions ≤1 cm (p = 0.36). The risk of radionecrosis at 12 months was 7.1% for all lesions, 13.2% for lesions >1 cm, and 3.2% for lesions ≤1 cm (p = 0.15). Conclusions: FSRT is safe and effective in the treatment of brain metastases of any size with excellent local control and toxicity outcomes. Prospective evaluation against single-fraction SRS is warranted for all lesion sizes. [ABSTRACT FROM AUTHOR]

Objectives: Patients undergoing stereotactic radiosurgery (SRS) for brain metastases require additional radiation for relapse. Our objective is to determine the factors associated with salvage SRS versus whole brain radiation therapy (WBRT) for salvage of first intracranial failure (ICF) after upfront SRS. Methods: We identified a cohort of 110 patients with brain metastases treated with SRS in the definitive or postoperative setting followed by subsequent salvage WBRT or SRS at least one month after initial SRS. Clinical and demographic characteristics were retrospectively recorded. Results: 78 Patients received SRS and 32 patients received WBRT at the time of first ICF. On multivariate analysis (MVA) factors associated with decreased use of salvage SRS were male gender (p=0.044) and local progression (p<0.001). Conclusions: Local progression and male gender were the strongest factors associated with selection of salvage WBRT. Possible etiologies of this difference could be provider or patient driven, but warrant further exploration. [ABSTRACT FROM AUTHOR]

Intracranial metastatic disease (IMD) is a prevalent complication of cancer that significantly limits patient survival and quality of life. Over the past half-century, our understanding of the epidemiology and pathogenesis of IMD has improved and enabled the development of surveillance and treatment algorithms based on prognostic factors and tumor biomolecular characteristics. In addition to advances in surgical resection and radiation therapy, the treatment of IMD has evolved to include monoclonal antibodies and small molecule antagonists of tumor-promoting proteins or endogenous immune checkpoint inhibitors. Moreover, improvements in the sensitivity and specificity of imaging as well as the development of new serological assays to detect brain metastases promise to revolutionize IMD diagnosis. In this review, we will explore current treatment principles in patients with IMD, including the emerging role of targeted and immunotherapy in select primary cancers, and discuss potential areas for further investigation. [ABSTRACT FROM AUTHOR]

Objective: Occurrence of brain metastases BM is associated with poor prognosis in patients with breast cancer (BC). Magnetic resonance imaging (MRI) is the standard of care in the diagnosis of BM and determines further treatment strategy. The aim of the present study was to evaluate the association between the radiographic markers of BCBM on MRI with other patients' characteristics and overall survival (OS). Methods: We included 88 female patients who underwent BCBM surgery in our institution from 2008 to 2019. Data on demographic, clinical, and histopathological characteristics of the patients and postoperative survival were collected from the electronic health records. Radiographic features of BM were assessed upon the preoperative MRI. Univariable and multivariable analyses were performed. Results: The median OS was 17 months. Of all evaluated radiographic markers of BCBM, only the presence of necrosis was independently associated with OS (14.5 vs 22.5 months, p = 0.027). In turn, intra-tumoral necrosis was more often in individuals with shorter time interval between BC and BM diagnosis (< 3 years, p = 0.035) and preoperative leukocytosis (p = 0.022). Moreover, dural affection of BM was more common in individuals with positive human epidermal growth factor receptor 2 status (p = 0.015) and supratentorial BM location (p = 0.024). Conclusion: Intra-tumoral necrosis demonstrated significant association with OS after BM surgery in patients with BC. The radiographic pattern of BM on the preoperative MRI depends on certain tumor and clinical characteristics of patients. [ABSTRACT FROM AUTHOR]

Copyright of Colombia Medica is the property of Universidad del Valle and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Stereotactic radiosurgery (SRS) has become a standard of care for the treatment of metastatic brain tumors (METs). Although a better balance of tumor control and toxicity of hypofractionated SRS (hfSRS) compared with single-fraction SRS (sfSRS) was demonstrated in large METs, there is no data comparing two approaches for small METs (< 4 cm3). It was aimed to compare clinical outcomes between sfSRS versus hfSRS Gamma Knife radiosurgery (GKRS) in a series of patients with unresected, small METs. Patients (n = 208) treated with sfGKRS or hfGKRS between June 2017 and May 2020 were retrospectively examined in a single center. The co-primary endpoints of local control (LC) and toxicity were estimated by applying the Kaplan–Meier method. Multivariate analysis using Cox proportional hazards (HR) modeling was used to assess the effect of independent variables on the outcomes. The actuarial LC rate was 99.7% at six months and 98.8% at 18 months in the sfGKRS group, and 99.4% and 94.3% in the hfGKRS group (p = 0.089), respectively. In multivariate analysis, MET volume (p = 0.023, HR 2.064) and biologically effective dose (BED10) (p < 0.0001, HR 0.753) was associated with LC. In total, treatment-related toxicity was observed in 13 (8.7%) patients during a median period of 10 weeks (range 1–31). Radiation necrosis was observed in four patients (1.9%), and all patients were in the sfGKRS group (p = 0.042). Only the maximum dose was associated with toxicity (p = 0.032, HR 1.047). Our current results suggest that hfGKRS is advantageous and beneficial also in patients with unresected, small METs. [ABSTRACT FROM AUTHOR]

Background: WBRT and systemic chemotherapy are the mainstay treatments for small-cell lung cancer (SCLC) brain metastases (BM). However, current recommendations are mainly based on evidence from retrospective analyses. A recent randomized trial found no benefits from WBRT compared with best supportive care (BSC) in patients with more than three BM from non-small-cell lung cancer (NSCLC). Herein, we aimed to evaluate the roles of WBRT and chemotherapy further in the management of BM from SCLC. Materials and Methods: There were 698 patients with BM from SCLC included. Of these, 580 received anti cancer treatment (Group 1), including 178 who received WBRT only (Group 1a), 129 who received chemotherapy only (Group 1b), and 273 who received WBRT plus chemotherapy (Group 1c). The other 118 received BSC (Group 2). Propensity score matching (PSM) analysis was used to compare Group 2 with each of the other groups. Results: After PSM, compared with Group 2 (n = 118), patients in Group 1 (n = 440) had a prolonged overall survival (OS) in both univariate and multivariate tests, with a median survival time of 10 months (95% CI = 9−11) in Group 1 and 3.5 months (95% CI = 2−7) in Group 2 (p < 0.001). In subgroup analyses, patients who received WBRT plus chemotherapy were more likely to benefit from treatment (p < 0.001). Chemotherapy alone or WBRT alone did not show survival benefits. Conclusion: WBRT plus chemotherapy improved OS in patients with BM from SCLC as compared to BSC. Chemotherapy alone and WBRT alone did not show survival benefits. This retrospective study suggests that SCLC patients with BM who receive WBRT combined with chemotherapy have a better outcome than those receiving BSC alone. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Oncology is the property of Chinese Journal of Oncology / Zhonghua Zhongliu Zazhi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Hypofractionated stereotactic radiosurgery has become an alternative for metastatic brain tumors (METs). We aimed to analyze the efficacy and safety of frameless hypofractionated Gamma Knife radiosurgery (hfGKRS) in the management of unresected, large METs. All patients who were managed with hfGKRS for unresected, large METs (> 4 cm3) between June 2017 and June 2020 at a single center were reviewed in this retrospective study. Local control (LC), progression-free survival (PFS), overall survival (OS), and toxicities were investigated. A total of 58 patients and 76 METs with regular follow-up were analyzed. LC rate was 98.5% at six months, 96.0% at one year, and 90.6% at 2 years during a median follow-up of 12 months (range, 2–37). The log-rank test indicated no difference in the distribution of LC for any clinical or treatment variable. PFS was 86.7% at 6 months, 66.6% at 1 year, and 58.5% at 2 years. OS was 81% at 6 months, 63.6% at one year, and 50.7% at 2 years. On the log-rank test, clinical parameters such as control status of primary cancer, presence of extracranial metastases, RTOG-RPA class, GPA group, and ds-GPA group were significantly associated with PFS and OS. Patients presented with grade 1 (19.0%), grade 2 (3.5%) and grade 3 (5.2%) side effects. Radiation necrosis was not observed in any patients. Our current results suggest that frameless hfGKRS for unresected, large METs is a rational alternative in selected patients with promising results. [ABSTRACT FROM AUTHOR]

Introduction: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy. Methods: We studied 439 patients with breast cancer and 1–10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan–Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis. Results: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03). Conclusions: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD. [ABSTRACT FROM AUTHOR]

Brain metastases (BM) are the most frequent intracranial tumors, which may result in significant morbidity and mortality when the lesions involve the perirolandic region. Surgical intervention for BM in the perirolandic region is still under discussion even though prompt relief of mass effect and avoidance of necrosis together with brain edema may not be achieved by radiotherapy. More recently, several researchers attempt to evaluate the benefit of surgery for BM within this pivotal sensorimotor area. Nevertheless, data are sparse and optimal treatment paradigm is not yet widely described. Since the advance in intraoperative neuroimaging and neurophysiology, resection of BM in the perirolandic region has been proven to be safe and efficacious, sparing this eloquent area while retaining reasonably low morbidity rates. Although management of BM becomes much more tailored and multimodal, surgery remains the cornerstone and principles of resection as well as indications for surgery should be well defined. This is the first review concerning the characteristics of BM involving the perirolandic region and the current impact of surgical therapy for the lesions. Future perspectives of advanced neurosurgical techniques are also presented. [ABSTRACT FROM AUTHOR]

Brain metastasis (BM), the most common adult brain tumor, develops in 20% to 40% of patients with late-stage cancer and traditionally are associated with a poor prognosis. The management of patients with BM has become increasingly complex because of new and emerging systemic therapies and advancements in radiation oncology and neurosurgery. Current therapies include stereotactic radiosurgery, whole-brain radiation therapy, surgical resection, laser-interstitial thermal therapy, systemic cytotoxic chemotherapy, targeted agents, and immune-checkpoint inhibitors. Determining the optimal treatment for a specific patient has become increasingly individualized, emphasizing the need for multidisciplinary discussions of patients with BM. Recognizing and addressing the sequelae of BMs and their treatment while maintaining quality of life and neurocognition is especially important because survival for patients with BMs has improved. The authors present current and emerging treatment options for patients with BM and suggest approaches for managing sequelae and disease recurrence. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine whether there is a difference in the efficacy of nivolumab in patients with advanced non-small cell lung cancer (NSCLC) presenting with or without brain metastases. Materials and methods: Patients with advanced NSCLC treated with nivolumab monotherapy were retrospectively analyzed. They were divided into two cohorts according to the presence or absence of brain metastases. The differences between the two cohorts in objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS) were investigated, and the intracranial efficacy, including intracerebral objective response rate (IORR), intracranial disease control rate (IDCR) and intracranial progression-free survival (iPFS), were examined in the brain metastasis (BM) cohort. Results: Seventy-three patients (32 with brain metastases and 41 without) were included. The ORRs of the BM cohort and the non-brain metastasis (non-BM) cohort were 25.0% and 19.5% (p = 0.574), DCRs were 53.1% and 56.1% (p = 0.800), respectively. Their median PFS were 2.8 and 4.9 months (p = 0.204), median DORs were 9.8 and 28.8 months (p = 0.003), and median OS were 14.8 and 20.2 months (p = 0.114), respectively. According to the Cox multivariate regression analysis, BM was not an independent prognostic factor. The IORR and IDCR of the BM cohort were 28.1% and 46.9%, respectively, with a median iPFS of 2.2 months. Conclusions: The efficacy of nivolumab is comparable in patients with NSCLC presenting with and without brain metastases, but the results must be verified in large-scale prospective studies. [ABSTRACT FROM AUTHOR]

Purpose of review: The purpose of this review is to highlight advances in the management of seizures in brain metastases from solid tumors. Recent findings: The highest risk for seizures is in patients with melanoma and lung cancer. There is lack of data on the efficacy of antiepileptic drugs (AEDs), but interactions between enzyme-inducing AEDs and anticancer agents must be avoided. Levetiracetam and valproic acid are the most appropriate drugs. Prophylaxis with AEDs for patients with brain metastases without a history of seizures is not recommended. Total resection of a brain metastasis allows complete seizure control. Seizures may represent an adverse effect of stereotactic radiosurgery or of high-dose chemotherapy. Summary: New preclinical and clinical studies should define the risk of brain metastasis in light of the new treatment options in the different tumor types. New clinical trials should be designed in patients with brain metastases in terms of treatment or prophylaxis of seizures. [ABSTRACT FROM AUTHOR]

Purpose: Given recently suggested utility of hypofractionated stereotactic radiosurgery (SRS) in treating large brain metastases (BMs) > 3 cm, we sought to prospectively control tumor size variable to investigate the efficacy and safety of hypofractionated SRS for medium-sized BMs (2.5 to 3 cm) compared with single-fraction SRS. Methods: Between 2011 and 2015, a total of 100 patients with newly diagnosed BMs (n = 105) of 2.5 to 3 cm had been treated with either single-fraction (n = 67; median dose 20 Gy) or hypofractionated SRS (n = 38; median cumulative dose 35 Gy in 5 daily fractions). No patients received any prior or upfront whole brain radiotherapy. In each patient, treatment outcome was measured by local tumor control (LTC), overall and progression-free survival (OS and PFS), and the occurrence of radiation necrosis (RN). Results: With a median follow-up of 14 months, significant differences were observed between the single-fraction versus hypofractionated SRS groups in the incidence of RN (29.9% vs. 5.3%, P < 0.001) and LTC (1-year LTC rates 66.6% vs. 92.4%, P = 0.028). There were no differences in PFS (median 6 months vs. 6 months, P = 0.381) and OS (median 13 months vs. 18 months, P = 0.239). Treatment-related adverse events (≥ grade 2 toxicity by CTCAE ver. 4.0) occurred more frequently in single-fraction group, although the difference did not reach statistical significance (56.3% vs. 36.1%, P = 0.084). Conclusions: Our results suggest a better safety and efficacy profile of hypofractionated SRS for medium-sized BMs compared with single-fraction SRS. Further prospective studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Purpose: The present study aims to conduct a systematic review of literature reporting on the dose and dosing schedule of dexamethasone (DXM) in relation to clinical outcomes in malignant brain tumor patients, with particular attention to evidence-based practice. Methods: A systematic search was performed in PubMed, Embase, Web of Science, Cochrane, Academic Search Premier, and PsycINFO to identify studies that reported edema volume reduction, symptomatic relief, adverse events and survival in relation to dexamethasone dose in glioma or brain metastasis (BM) patients. Results: After screening 1812 studies, fifteen articles were included for qualitative review. Most studies reported a dose of 16 mg, mostly in a schedule of 4 mg four times a day. Due to heterogeneity of studies, it was not possible to perform quantitative meta-analysis. For BMs, best available evidence suggests that higher doses of DXM may give more adverse events, but may not necessarily result in better clinical condition. Some studies suggest that higher DXM doses are associated with shorter survival in the palliative setting. For glioma, DXM may lead to symptomatic improvement, yet no studies directly compare different doses. Results regarding edema reduction and survival in glioma patients are conflicting. Conclusions: Evidence on the safety and efficacy of different DXM doses in malignant brain tumor patients is scarce and conflicting. Best available evidence suggests that low DXM doses may be noninferior to higher doses in certain circumstances, but more comparative research in this area is direly needed, especially in light of the increasing importance of immunotherapy for brain tumors. [ABSTRACT FROM AUTHOR]

Background and Purpose: To date, imaging studies quantifying the amount of vasogenic edema reduction (VE) in patients with brain metastases (BM) treated with glucocorticoids (GC) have included a very limited number of patients and showed ambiguous results. Here, we aim to determine the radiological effect of GC on VE in BM patients in a large cohort with multiple primary tumor entities in a cross-sectional approach. Materials and Methods: This monocentric retrospective study includes 299 patients first-ever diagnosed with 2,759 intra-axial BM on the respective MRI. 126/299 patients received GC prior to MRI due to mass effect of edema on cranial CT scan and clinical symptoms (GC-pos) and 173 patients did not (GC-neg). GC dose was documented in 85/126 patients. All BM and their respective VE were semi-automatically segmented on post-contrast T1-weighted images. Results: VE volumes were higher in GC-pos compared to GC-neg (p = 0.009) and did not correlate with GC dose. Multivariate linear regression analysis with interaction terms on the assumption that BM volume and BM number influence the probability of GC administration shows that large and higher numbers of BM under GC treatment generate less VE than without (p < 0.001 and p = 0.038, respectively). The primary tumor type and total BM volume did not influence VE volume. Conclusion: Use of GC is especially effective for treatment of VE formation in patients with larger and multiple BM regardless of primary tumor type and dosage. However, based on the present data a direct causative relationship between GC and VE cannot be proven. [ABSTRACT FROM AUTHOR]

Introduction: Brain metastases (BM) have a very poor prognosis, creating a demand for effective local therapies, such as radiotherapy (RT) and neurosurgery, the combination of which is debatable. The aim of the present study was to investigate prognostic factors and to develop treatment recommendations for patients with BM. Material and Methods: A total of 84 patients treated between May 2011 and July 2016 were analyzed in a single-institution retrospective study. Results: Overall survival (OS) was 10.3 months. Poor OS was defined by a Karnofsky performance index of =70% (2.9 vs. 15.8 months; p = 0.009), male gender (6.5 vs. 18.3 months; p = 0.044), and incomplete neurosurgical resection (2.5 vs. 15.8 months; p = 0.017). These factors were also shown to be significant in univariate analysis, while only radical resection remained significant in multivariate testing (p = 0.023). A direct comparison between whole-brain RT (with or without boost) and local RT illustrated a superior OS for local therapy (22.7 vs. 9.5 months; p = 0.022), especially in case of up to 3 metastases (p = 0.041). Intracranial control was 81% with a median duration of 31.6 months. Conclusion: Combined modality treatment of RT and neurosurgery is effective and feasible. A complete removal of all metastases is the cardinal prognostic factor. [ABSTRACT FROM AUTHOR]

Short‑term efficacy, adverse effects and the impact on quality of life (QoL) of a concomitant treatment with intensity‑modulated radiation therapy (IMRT) and temozolomide (TMZ) in patients with brain metastases (BMs) from lung adenocarcinoma were evaluated. This study sought to confirm the benefit of adding TMZ to IMRT in patients with BMs from lung adenocarcinoma. Nine patients were enrolled and received a dose of 30 Gy in 10 daily fractions to clinical tumor volume (CTV) according to IMRT, then additional dose of 9 Gy in 3 fractions of IMRT was delivered to gross tumor volume (GTV) only with concomitant TMZ (75 mg/m2/day) orally during RT for 3 weeks. One patient achieved complete response (CR) (11.1%), 6 patients obtained partial response (PR) (66.7%), and there were no patients in progression. Therefore, objective response (OR) reached 77.8%. The main adverse effects included neutropenia, anemia, vomiting, fatigue and dizziness. Grade ≥3 of hematologic toxicities did not occur. However, the other 9 patients who received only intensity‑modulated radiation had much worse results. The CR was 0, PR rate was 44.4%, OR rate was 44.4%. The results indicated that the benefit of adding TMZ to IMRT was confirmed in patients with BMs from lung adenocarcinoma. The treatment was active, a significant OR was observed, and achieved an improvement in QoL demonstrated by QoL grade (p<0.05). [ABSTRACT FROM AUTHOR]

Advances in chemotherapy and targeted therapies have improved survival in cancer patients with an increase of the incidence of newly diagnosed brain metastases (BMs). Intracranial metastases are symptomatic in 60-70% of patients. Magnetic resonance imaging (MRI) with gadolinium is more sensitive than computed tomography and advanced neuroimaging techniques have been increasingly used in the detection, treatment planning, and follow-up of BM. Apart from the morphological analysis, the most effective tool for characterizing BM is immunohistochemistry. Molecular alterations not always reflect those of the primary tumor. More sophisticated methods of tumor analysis detecting circulating biomarkers in fluids (liquid biopsy), including circulating DNA, circulating tumor cells, and extracellular vesicles, containing tumor DNA and macromolecules (microRNA), have shown promise regarding tumor treatment response and progression. The choice of therapeutic approaches is guided by prognostic scores (Recursive Partitioning Analysis and diagnostic-specific Graded Prognostic Assessment-DS-GPA). The survival benefit of surgical resection seems limited to the subgroup of patients with controlled systemic disease and good performance status. Leptomeningeal disease (LMD) can be a complication, especially in posterior fossa metastases undergoing a "piecemeal" resection. Radiosurgery of the resection cavity may offer comparable survival and local control as postoperative whole-brain radiotherapy (WBRT). WBRT alone is now the treatment of choice only for patients with single or multiple BMs not amenable to surgery or radiosurgery, or with poor prognostic factors. To reduce the neurocognitive sequelae of WBRT intensity modulated radiotherapy with hippocampal sparing, and pharmacological approaches (memantine and donepezil) have been investigated. In the last decade, a multitude of molecular abnormalities have been discovered. Approximately 33% of patients with non-small cell lung cancer (NSCLC) tumors and epidermal growth factor receptor mutations develop BMs, which are targetable with different generations of tyrosine kinase inhibitors (TKIs: gefitinib, erlotinib, afatinib, icotinib, and osimertinib). Other "druggable" alterations seen in up to 5% of NSCLC patients are the rearrangements of the "anaplastic lymphoma kinase" gene TKI (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib). In human epidermal growth factor receptor 2-positive, breast cancer targeted therapies have been widely used (trastuzumab, trastuzumab-emtansine, lapatinib-capecitabine, and neratinib). Novel targeted and immunotherapeutic agents have also revolutionized the systemic management of melanoma (ipilimumab, nivolumab, pembrolizumab, and BRAF inhibitors dabrafenib and vemurafenib). [ABSTRACT FROM AUTHOR]

The exclusion of “real-world” patients from registration clinical trials of cancer immunotherapy represents a significant emerging issue. For instance, a large fraction of cancer patients develops brain metastases during the course of the disease, but results from large prospective clinical trials investigating this considerable proportion of the cancer patient population are currently lacking. To provide a useful tool for the clinician in a “real-world” setting, we have reviewed the available literature regarding the safety and efficacy of immune check-point inhibitors in patients with cancer metastatic to the brain. Overall, these data provide encouraging evidence that these therapeutic agents can induce intracranial objective responses, particularly in patients with asymptomatic and previously untreated brain metastases. Larger prospective studies are needed to confirm these initial results. [ABSTRACT FROM AUTHOR]

Background: Malignant melanoma brain metastases (MBM) are the third most common cause for brain metastases (BM). Historically Whole-brain radiotherapy (WBRT) was considered the goldstandard of treatment even though melanoma cells are regarded as very radioresistant. Therapeutic possibilities have fundamentally changed since the availability of stereotactic radiotherapy (SRT), where it is possible to apply high ablative doses in a very precise manner. In this work we analyze prognostic factors of overall survival (OS) after SRT in patients with MBM and evaluate the applicability of popular prognostic indices that mainly stem from the WBRT-era.Materials and Methods: This work is a retrospective analysis of OS of 80 malignant melanoma (MM) patients who received SRT for intracranial melanoma metastases between 2004 and 2014 who had not received prior treatment for MBM in terms of surgery or WBRT. Potential prognostic factors were analyzed using univariable and multivariable analysis. Existing prognostic scores [Graded Prognostic Assessment (GPA), Diagnosis-Specific-GPA (DS-GPA), Golden Grading System (GGS) and RADES] were calculated and tested using log-rank analysis.Results: Eighty patients, respectively 177 brain metastases, were irradiated. The median survival time from radiation was 7.06 months. Overall, GGS, GPA and DS-GPA were significant predictors of survival. The MM-specific index DS-GPA showed the best p-value but did not show adequate division when looking at the two intermediate risk subgroups. RADES did not show any statistically significant prognostic value. In univariable as well as in multivariable analyses a higher Karnofsky-Index, a single BM, and non nodular melanoma (NM) histology were positive predictors of survival.Conclusion: The existing prognostic scores do not seem to ideally fit for this special group of patients. Our results indicate that the histologic subtype of MM could add to the prognostic value of specialized future indices. [ABSTRACT FROM AUTHOR]

Radiation necrosis is a serious potential adverse event of stereotactic radiosurgery that cannot be reliably differentiated from recurrent tumor using conventional imaging techniques. Intravoxel incoherent motion (IVIM) is a magnetic resonance imaging (MRI) based method that uses a diffusion-weighted sequence to estimate quantitative perfusion and diffusion parameters. This study evaluated the IVIM-derived apparent diffusion coefficient (ADC) and perfusion fraction (f), and compared the results to the gold standard histopathological-defined outcomes of radiation necrosis or recurrent tumor. Nine patients with ten lesions were included in this study; all lesions exhibited radiographic progression after stereotactic radiosurgery for brain metastases that subsequently underwent surgical resection due to uncertainty regarding the presence of radiation necrosis versus recurrent tumor. Pre-surgical IVIM was performed to obtain f and ADC values and the results were compared to histopathology. Five lesions exhibited pathological radiation necrosis and five had predominantly recurrent tumor. The IVIM perfusion fraction reliably differentiated tumor recurrence from radiation necrosis (f = 10.1 ± 0.7 vs. 8.3 ± 1.2, p = 0.02; cutoff value of 9.0 yielding a sensitivity/specificity of 100%/80%) while the ADC did not distinguish between the two (ADC = 1.1 ± 0.2 vs. 1.2 ± 0.4, p = 0.6). IVIM shows promise in differentiating recurrent tumor from radiation necrosis for brain metastases treated with radiosurgery, but needs to be validated in a larger cohort. [ABSTRACT FROM AUTHOR]

Previous studies have been conducted on the prognostic factors for overall survival in patients with brain metastases (BMs) following whole brain radiotherapy (WBRT). However, there have been a small number of studies regarding the prognostic factors for the response of tumor to WBRT. The aim of the present study was to identify the predictive factors for the response to WBRT from the point of view of reduction of tumor using magnetic resonance imaging. A retrospective analysis of 62 patients with BMs from primary lung cancer treated with WBRT was undertaken. The effects of the following factors on the response to WBRT were evaluated: Age; sex; performance status; lactate dehydrogenase; pathology; existence of extracranial metastases; activity of extracranial disease; chemo‑history; chest radiotherapy history; treatment term; γ‑knife radiotherapy; diffusion weighted image signal intensity; tumor diameter; extent of edema and the edema/tumor (E/T) ratio. The association between the reduction of tumors and clinical factors was evaluated using logistic regression analysis. P<0.05 was considered to indicate a statistically significant difference. The overall response ratio of this cohort was 54.8%. In the univariate analysis, the response of tumors was associated with the presence of small cell lung carcinoma (SCLC; P=0.0007), an E/T ratio of ≥1.5 (P=0.048), and a median tumor diameter of <20 mm (P=0.014). In the multivariate analysis, the presence of SCLC [P=0.001; odds ratio (OR), 17.152), an E/T ratio of ≥1.5 (P=0.019; OR, 9.526), and the presence of extracranial metastases (P=0.031; OR, 4.875) were revealed to be independent predictive factors for the reduction of tumor. The following 3 factors were significantly associated with the response of tumors to WBRT: The presence of SCLC; an E/T ratio of ≥1.5; and the presence of extracranial metastases. The E/T ratio is a novel index that provides a simple and easy predictive method for use in a clinical setting. [ABSTRACT FROM AUTHOR]

Background: Brain metastasis (BM) is a poor prognostic factor for non-small-cell lung cancer (NSCLC). The efficacy and roles of combining temozolomide (TMZ) with whole brain radiotherapy (WBRT) in protection neurocognitive function (NCF) and improvement quality of life (QOL) were investigated and compared with WBRT alone in the treatment of NSCLC patients with BM.Methods: A total of 238 NSCLC patients with BM were reviewed and categorized into WBRT plus TMZ (RCT) arm and WBRT alone (RT), respectively. The efficacy was evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model. NCF was assessed by using revised Hopkins Verbal Learning Test (HVLT-R), Controlled Oral Word Association (COWA) test and Trail-making Test (TMT). QOL was assessed by the Functional Assessment of Cancer Treatment-Lung (FACT-L) Chinese version 4.0 questionnaire.Results: The average intracranial objective response (ORR) and disease control rate (DCR) for all the patients were 26.9 and 95.8%, respectively. The intracranial ORR and DCR for RCT and RT arm were 34.9% vs. 20.2% (p = 0.01) and 98.4% vs. 92.7% (p = 0.03), respectively. The median intracranial progression-free survival (PFS) and overall survival (OS) of NSCLC patients with BM were 5.2 and 7.3 months, respectively. The median PFS of RCT arm was significantly longer than that of RT arm (5.9 vs. 4.9 months, p = 0.002). The median OS of the RCT arm was also slightly longer than that of the RT arm (8.5 vs. 5.9 months), but without statistical significance (p = 0.11). Multivariate analysis indicated that TMZ was a significant factor for PFS. Statistically significant differences on NCF and QOL were observed between CRT and RT arms at 5 months. RCT showed a trend of toxicities increase compared with RT, however, the toxicities were tolerable and manageable.Conclusions: Adding TMZ to WBRT in the treatment of NSCLC patients with BM could improve the intracranial ORR, DCR, and median PFS compared with WBRT alone. Although no remarkable difference on median OS was found, adding TMZ could prevent NCF and QOL from worsening. The side effects increased by adding TMZ, but the difference was not statistical significance and toxicities were well tolerated. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate vinorelbine drug exposure and activity in brain metastases of the human MDA-MB-231BR breast cancer model using integrated imaging and analysis. Methods: Brain and systemic metastases were created by administration of cancer cells in female NuNu mice. After metastases developed, animals were administered vinorelbine at the maximal tolerated dose (12 mg/kg), and were evaluated thereafter for total and unbound drug pharmacokinetics, biomarker TUNEL staining, and barrier permeability to Texas red. Results: Median brain metastasis drug exposure was 4-fold greater than normal brain, yet only ~8% of non-barrier systemic metastases, which suggests restricted brain exposure. Unbound vinorelbine tissue/plasma partition coefficient, K, equaled ~1.0 in systemic metastases, but 0.03-0.22 in brain metastases, documenting restricted equilibration. In select sub-regions of highest drug-uptake brain metastases, K approached 1.0, indicating complete focal barrier breakdown. Most vinorelbine-treated brain metastases exhibited little or no positive early apoptosis TUNEL staining in vivo. The in vivo unbound vinorelbine IC for TUNEL-positive staining (56 nM) was 4-fold higher than that measured in vitro (14 nM). Consistent with this finding, P-glycoprotein expression was observed to be substantially upregulated in brain metastasis cells in vivo. Conclusions: Vinorelbine exposure at maximum tolerated dose was less than one-tenth that in systemic metastases in >70% of brain metastases, and was associated with negligible biomarker effect. In small subregions of the highest uptake brain metastases, compromise of blood-tumor barrier appeared complete. The results suggest that restricted delivery accounts for 80% of the compromise in drug efficacy for vinorelbine against this model. [ABSTRACT FROM AUTHOR]

Although human epidermal growth factor receptor 2 (HER2)-targeted therapy significantly improves the prognosis of patients with HER2-positive breast cancer, most patients with advanced breast cancer eventually progress due to drug resistance. At present, there is no standard treatment after patients become resistant to HER2-targeted therapy. Previous studies have indicated that anti-angiogenesis drugs have potential efficacy in the treatment of advanced breast cancer. The present study reported on a case of a pretreated patient with HER2-positive advanced breast cancer with brain metastases who developed resistance to multiple lines of HER2-targeted treatment. The patient was treated with apatinib combined with trastuzumab and albumin-bound paclitaxel. The patient achieved partial response to the third-line treatment with a progression-free survival of 9 months. After combination treatment, the symptoms of headache and vomiting were relieved and all the brain metastases were significantly reduced. The present case indicated that apatinib may have anti-tumor activity in patients with HER2-positive breast cancer with HER2-targeted drug resistance. The present case provides valuable information and may offer a new possibility for the treatment of patients with breast cancer with brain metastases who progressed after clinical treatment with small-molecule anti-HER2 tyrosine kinase inhibitor drugs. [ABSTRACT FROM AUTHOR]

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Objective: The intention of this study is to compare whole brain radiotherapy and stereotactic radiosurgery (WBRT + SRS) with WBRT in patients with 1-4 brain metastases to find a subgroup of patients that have a great benefit with aggressive treatment.Materials and Methods: Between December 2002 and December 2013, 60 patients with 1-4 brain metastases were treated by WBRT + SRS. In this period, 60 patients treated with WBRT were matched with patients treated with WBRT + SRS.Results: The median survival for the entire cohort was 8.3 months. In the univariate analysis, WBRT + SRS (0.031), the presence of extracranial disease (P = 0.02), Karnofsky performance score <70 (P = 0.0001), and age >65 (P = 0.001) years were significant factors for survival. In the entire cohort, the median survival for recursive partitioning analysis (RPA) classes I, II, and III was 11, 7, and 3 months, respectively (P = 0.0001). In a stratified analysis, only RPA class I achieved statistical significance for 1-year survival between the groups (WBRT + SRS = 51% and WBRT = 23%, P = 0.03). Cox regression analysis revealed WBRT + SRS, age >65 years, and extracranial disease as independent prognostic factors. In the univariate analysis, lesion volume ≤5 cm 3 (P = 0.002) and WBRT + SRS (P = 0.003) were the significant factors associated with better brain control.Conclusion: WBRT plus SRS was an independent prognostic factor for survival. However, the combined treatment appears to be justified only in patients with RPA I and lesion volume ≤5 cm 3, independently of the number of lesions. [ABSTRACT FROM AUTHOR]

It is not uncommon for brain metastasis (BM) treated with stereotactic radiosurgery (SRS) to demonstrate radiographic enlargement, with the patient developing neurological deficits attributable to a lesion at the site of SRS. The management of both local recurrence and radiation-induced necrosis (RN) poses a significant therapeutic dilemma, if surgical resection is not feasible, and effective therapies have yet to be established. This preliminary study introduces our initial experience with salvage SRS using adjuvant bevacizumab for this refractory entity. We retrospectively reviewed five patients who had received salvage SRS using adjuvant bevacizumab for recurrent BM complicated by RN. The diagnosis was based on clinical features, serial imaging studies and/or histopathological findings. Patients underwent salvage SRS followed by the first cycle of bevacizumab (7.5-10 mg/kg intravenous). Bevacizumab was repeated every 3-4 weeks until tumor progression or significant toxic events. The number of bevacizumab doses ranged from 2 to 16 (median 4). Follow-up MR imaging demonstrated a clear radiographic response in all lesions. Neurological symptoms improved in three patients and stabilized in two. In two patients, bevacizumab treatment was discontinued due to anemia and gastrointestinal bleeding, respectively. At the time of data analysis, four patients had died and the other was still alive. The causes of death were neurological decline and systemic disease progression in two patients each. Salvage SRS with adjuvant bevacizumab use appeared to provide an adequate radiographic response as well as neurological palliation for selected patients with heavily treated recurrent BM complicated by RN. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the cost-effectiveness of surgical resection (S) and Cesium-131 (Cs-131) [S + Cs-131] intraoperative brachytherapy versus S and stereotactic radiosurgery (SRS) [S + SRS] for the treatment of brain metastases. Treatment records as well as hospital and outpatient charts of 49 patients with brain metastases between 2008 and 2012 who underwent S + Cs-131 (n = 24) and S + SRS (n = 25) were retrospectively reviewed. Hospital charges were compared for the single treatment in question. Means and curves of survival time were defined by the Kaplan-Meier estimator, with the cost analysis focusing on the time period of the relevant treatment. Quality adjusted life years (QALY) and Incremental cost-effectiveness ratios (ICER) were calculated for each treatment option as a measure of cost-effectiveness. The direct hospital costs of treatments per patient were: S + Cs131 = $19,271 and S + SRS = $44,219. The median survival times of S + Cs-131 and S + SRS were 15.5 and 11.3 months, and the 12 month survival rates were 61 % and 49 % (P = 0.137). The QALY for S + SRS when compared to S + Cs-131 yielded a p < 0.0001, making it significantly more cost-effective. The ICER also revealed that when compared to S + Cs-131, S + SRS was significantly inferior (p < 0.0001). S + Cs-131 is more cost-effective compared with S + SRS based on hospital charges as well as QALYs and ICER. Cost effectiveness, in addition to efficacy and risk, should factor into the comparison between these two treatment modalities for patients with surgically resectable brain metastases. [ABSTRACT FROM AUTHOR]

Brain metastases (BM) are the most common brain tumors of adults and are associated with fatal prognosis. Formation of new blood vessels, named angiogenesis, was proposed to be the main hallmark of the growth of BM. Previous preclinical evidence revealed that angiogenic blockage might be considered for treatment; however, there were varying responses. In this study, we aimed to characterize the expression pattern of angiogenesis-related genes in BM of lung cancer and melanoma, which might be of importance for the different responses against anti-angiogenic treatment. Fifteen snap-frozen tissues obtained from BM of non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and melanoma patients were analyzed for angiogenesis-related genes using a commercially available gene expression kit. Epilepsy tissue was used as control. Expression values were analyzed using hierarchical clustering investigating relative fold changes and mapping to Omicsnet protein interaction network. CXCL10, CEACAM1, PECAM1, KIT, COL4A2, COL1A1, and HSPG2 genes were more than 50-fold up-regulated in all diagnosis groups when compared to control, whereas genes such as ANGPT4, PDGFRB, and SERPINF1 were down-regulated only in SCLC and melanoma groups, respectively. Using hierarchical clustering, 12 out of 15 cases were allocated to the correct histological primary tumor type. We identified genes with consistent up-regulation in BM of lung cancer and melanoma and other genes with differential expression across BM of these tumor types. Our data may be of relevance for targeted therapy or prophylaxis of BM using anti-angiogenic agents. [ABSTRACT FROM AUTHOR]

Background: Our purpose was to analyze the long-term clinical outcome and to identify prognostic factors after Linac-based stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) on patients with brain metastases (BM) from non-small cell lung cancer (NSCLC).Materials and Methods: We performed a retrospective analysis of survival on 90 patients who underwent SRS or FSRT of intracranial NSCLC metastases between 04/2004 and 05/2014 that had not undergone prior surgery or whole brain radiotherapy (WBRT) for BM. Follow-up data was analyzed until May 2015. Potential prognostic factors were examined in univariable and multivariable analyses. The Golden Grading System (GGS), the disease-specific graded prognostic assessment (DS-GPA), the RADES II prognostic index as well as the NSCLC-specific index proposed by Rades et al. in 2013 (NSCLC-RADES) were calculated and their predictive values were tested in univariable analysis.Results: The median follow-up time of the surviving patients was 14 months. The overall survival (OS) rate was 51 % after 6 months and 29.9 % after 12 months. Statistically significant factors of better OS after univariable analysis were lower International Union Against Cancer (UICC) stage at first diagnosis, histology of adenocarcinoma, prior surgery of the primary tumor and lower total BM volume. After multivariable analysis adenocarcinoma histology remained a significant factor; higher Karnofsky Performance Score (KPS) and the presence of extracranial metastases (ECM) were also significant. The RADES II and the NSCLC-RADES indices were significant predictors of OS. However, the NSCLC-RADES failed to differentiate between intermediate- and low-risk patients. The DS-GPA and GGS were not statistically significant predictors of survival in univariable analysis.Conclusion: The ideal prognostic index has not been defined yet. We believe that more specific indices will be developed in the future. Our results indicate that the histologic subtype of NSCLC could add to the prognostic value of specialized future indices. The RADES II index had the highest predictive value in the examined patient cohort. [ABSTRACT FROM AUTHOR]

Background: In this study, we compared the dosimetric properties between Gamma Knife (GK) and Cyberknife (CK), and investigated the clinical implications in treating brain metastases (BMs). Methods: Between 2011 and 2013, 77 patients treated with either single-fraction GK for small BMs ( n = 40) or fractionated CK for large BMs >3 cm ( n = 37) were analyzed. Among a total of 160 lesions, 81 were treated with GK (median, 22 Gy) and 38 (large lesions) with three- or five-fraction CK (median, 35 Gy). The median tumor volume was 1.0 cc (IQR, 0.12-4.4 cc) for GK and 17.6 cc (IQR, 12.8-23.7 cc) for fractionated CK. A lesion-to-lesion dosimetric comparison was performed using the identical contour set in both systems. Results: The mean dose to tumor was significantly higher in GK by 1.25-fold ( P < 0.001), whereas normal tissue volume receiving 90-10 % of prescription dose was significantly larger in CK by 1.26-fold ( P < 0.001). Nevertheless, no differences were observed in local tumor control (rates at 1 year, 89.7 % vs 87.0 %; P = 0.594) and overall survival (median, 14 vs 16 months; P = 0.493) between GK and fractionated CK groups. The incidences of radiation necrosis were also not different (12.3 % vs 15.8 %; P = 0.443). Conclusions: Despite slightly inferior dosimetric properties of CK, fractionated CK for large BMs appears to be as effective and safe as single-fraction GK for small BMs, representing fractionation as an effective strategy for enhancing efficacy and moderating toxicity in stereotactic radiosurgery for BMs. [ABSTRACT FROM AUTHOR]

Introduction: Quality of life (QOL) is an important treatment endpoint in advanced cancer patients with brain metastases. In clinical trials, statistically significant changes can be reached in a large enough population; however, these changes may not be clinically relevant. Objective: The objective of this study was to determine the minimal clinically important difference (MCID) for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire brain module (EORTC QLQ-BN20) in patients with brain metastases. Methods: Patients undergoing radiotherapy for brain metastases completed the EORTC QLQ-BN20 and QLQ-C30/C15-PAL at baseline and 1-month follow-up. MCIDs were calculated for both improvement and deterioration using anchor- and distribution-based approaches. The anchor of overall QOL (as assessed by question 30 or question 15 on the QLQ-C30 and QLQ-C15-PAL, respectively) was used to determine meaningful change. Results: A total of 99 patients were included. The average age was 61 years, and the most common primary cancer sites were the lung and breast. Statistically significant meaningful differences were seen on two scales. A decrease of 6.1 (95 % confidence interval (CI) 0.8 to 11.4) units and 13.8 (0.2 to 27.4) units was required to represent clinically relevant deterioration of seizures and weakness of legs, respectively. Distribution-based MCID estimates tended to be closer to 0.5 SD on the EORTC QLQ-BN20. Conclusion: Understanding MCIDs allows physicians to determine the impact of treatment on patients' QOL and allows for determination of sample sizes for clinical trials. Future studies should be conducted to validate our findings in a larger population of patients with brain metastases. [ABSTRACT FROM AUTHOR]

Purpose: To show the clinical results of the treatment of brain metastases via radiosurgery using Volumetric Modulated Arc Therapy (VMAT). Materials and methods: 52 patients having lung (62 %), breast (17 %), colorectal (8 %) and other cancers (13 %) with one to three brain metastases were treated with 5 non-coplanar VMAT arcs. The treatment dose varied from 12 to 20 Gy, administered in one single session. The volume of metastases ranged from 0.04 to 24.92 cc. Radiosurgery alone was used for 54 % of cases, while 19 % received whole brain radiotherapy due to relapse. Patients were classified according to the Disease-specific graded prognostic assessment (DS-GPA) index and survival was assessed via the Kaplan-Meier model. Results: The median survival time was 7.2 months from the date of radiosurgery. The Karnofsky and DS-GPA indices were the most significant with regard to survival. Patients with a Karnofsky performance status (KPS) over 70 had a longer survival time of 9.2 months, as opposed to those with a KPS below 70 of 3.5 months. No significant differences were found with regard to the type of cancer or the number of lesions. Local tumour control was achieved for 42 metastases (82 %), of which a complete response was achieved for 7 lesions, a partial response for 21; 15 lesions were stabilized. Local progression was observed in 8 lesions (15 %). The median treatment time per patient was 29 min. Conclusions: The VMAT technique proves to be safe and effective for treating brain metastases via radiosurgery. [ABSTRACT FROM AUTHOR]

Purpose: Despite advances in multimodality management of brain metastases, local progression following stereotactic radiosurgery (SRS) can occur. Often, surgical resection is favored, as it frequently provides immediate symptom relief as well as pathological characterization of any residual tumor. Should the pathological specimen contain viable tumor cells, further radiation therapy is an option to sterilize the tumor bed. We evaluated the use of repeat SRS (rSRS) in lieu of whole-brain radiation therapy (WBRT) as a means of improving local control (LC) while minimizing potential toxicity and dose to the normal brain. Materials/methods: A retrospective review was performed to identify patients with brain metastases who underwent SRS and then surgical resection for locally recurrent or persistent disease. From 2004 to 2014, 13 consecutive patients or 15 lesions were treated with rSRS after resection, either post-operatively to the tumor bed (n D10, 66.6%) or after a second local recurrence (nD5, 33.3%). LC, distant brain failure (DBF), and radiation toxicity were determined using patient records, RECIST criteria v1.1, and CTCAE v4.03. Results: At a median follow-up interval of 9.0 months (range 1.8-54.9 months) from time of rSRS, five patients remain alive. Following rSRS, 13 of the 15 (86.6%) lesions were locally controlled with an estimated 100% LC at 6 months and 75% LC at 1 year. However, 11 of the 15 (73.3%) treated lesions developed DBF after rSRS with 3 of 13 patients proceeding toWBRT. Two of 15 (13.3%) resulted in either grade 2 radionecrosis with grade 3 seizures or grade 3 radionecrosis. Conclusion: Repeat SRS represents a potential salvage therapy for patients with locally recurrent brain metastases, providing additional tumor control with acceptable toxicity, even in the setting of prior SRS and surgical resection. rSRS may be reasonable to use as an alternative to WBRT in this setting. [ABSTRACT FROM AUTHOR]

Background: This study compared the efficacy of two commonly used fractionation schedules for palliative whole brain irradiation in patients with brain metastases, and assessed the association of the Radiotherapy Therapy Oncology Group (RTOG) Recursive Partitioning Analysis for brain metastases (RPA) to survival with each schedule. Methods: Patients with multiple (more than three) brain metastases were assigned to receive whole brain irradiation in 20 Gy over 5 fractions (group 1) or 30 Gy over 10 fractions (group 2). Primary outcome was response and overall survival in each group. Secondary outcome was the RPA classification relation to overall survival and its possible role in the choice between schedules. Results: There were 54 patients in group 1 and 39 in group 2. There was no significant difference in response (P=0.67) or overall survival between the two groups (P=0.55). However RPA 1 patients had significantly better overall survival than RPA 2 patients in both group 1 (P=0.02) and group 2 (P=0.0014), but no significant difference was found when overall survival of RPA 1 patients of both groups were compared (P=0.47) or that of RPA 2 patients in both groups (P=0.29). Conclusion: The two schedules assessed are comparable in terms of response and overall survival. RPA 1 patients have better overall survival than RPA 2 patients regardless of the fractionation used. A schedule of 20 Gy over 5 fractions should be routinely considered for RPA 2 patients as they are less likely to experience late toxicity. This schedule may be considered for RPA 1 patients, however larger randomized trials are needed to confirm the results and assess differences in neurocognitive function. [ABSTRACT FROM AUTHOR]

Aim We aimed to characterize angiogenesis and proliferation and their correlation with clinical characteristics in a large brain metastasis ( BM) series. Methods Ki67 proliferation index, microvascular density ( MVD) and hypoxia-inducible factor 1 alpha ( HIF-1 alpha) index were determined by immunohistochemistry in BM and primary tumour specimens. Results Six hundred thirty-nine BM specimens of 639 patients with lung cancer (344/639; 53.8%), breast cancer (105/639; 16.4%), melanoma (67/639; 10.5%), renal cell carcinoma ( RCC; 52/639; 8.1%) or colorectal cancer ( CRC; 71/639; 11.1%) were available. Specimens of the corresponding primary tumour were available in 113/639 (17.7%) cases. Median Ki67 index was highest in CRC BM and lowest in RCC BM ( P < 0.001). MVD and HIF-1 alpha index were both highest in RCC BM and lowest in melanoma BM ( P < 0.001). Significantly higher Ki67 indices, MVD and HIF-1 alpha indices in the BM than in matched primary tumours were observed for breast cancer, non-small cell lung cancer ( NSCLC) and CRC. Correlation of tissue-based parameters with overall survival in individual tumour types showed a favourable and independent prognostic impact of low Ki67 index [hazard ratio ( HR) 1.015; P < 0.001] in NSCLC BM and of low Ki67 index ( HR 1.027; P = 0.008) and high angiogenic activity ( HR 1.877; P = 0.002) in RCC. Conclusion Our data argue for differential pathobiological and clinical relevance of Ki67 index, HIF1-alpha index and MVD between primary tumour types in BM patients. An independent prognostic impact of tissue-based characteristics was observed in patients with BM from NSCLC and RCC, supporting the incorporation of these tissue-based parameters into diagnosis-specific prognostic scores. [ABSTRACT FROM AUTHOR]

Brain metastases (BM) are a common and lethal complication of non-small cell lung cancer (NSCLC), which portend a poor prognosis. In addition, their management implies several challenges including preservation of neurological and neurocognitive function during surgery or radiation-therapy, minimizing iatrogenic complications of supportive medications, and optimizing drug delivery across the blood-brain barrier. Despite these challenges, advancements in combined modality approaches can deliver hope of improved overall survival and quality of life for a subset of NSCLC patients with BM. Moreover, new drugs harnessing our greater understanding of tumor biology promise to build on this hope. In this mini-review, we revised the management of BM in NSCLC including advancements in neurosurgery, radiation therapy, as well as systemic and supportive therapy. [ABSTRACT FROM AUTHOR]

Objective: Since brain metastases (BM) is often accompanied by edema, and endostatin (ES) can prevent tumor tissue edema, we investigated the therapeutic effects of ES combined with radiotherapy in the treatment of BM of NSCLC. We also determined the patients who are suitable for this therapy. Methods: Eighty patients with BM of NSCLC were randomly divided into combination group and radiotherapy alone group. The primary endpoint was overall response rate, and secondary endpoints were overall survival time, cerebral edema index and adverse reactions. These were observed and the expressions of vascular endothelial growth factor receptor 2 (VEGFR) protein and KDR gene in primary lesions were detected with immunohistochemical method and fluorescence in situ hybridization. Results: Compared with radiotherapy alone, brain edema was significantly reduced in the ES group ( P = 0.003) without marked adverse reactions. For the overall response rate, there was no statistical significant difference between the two groups (control, 90 % vs. ES, 75 %, P = 0.07), but there was statistical significance in the patients with positive VEGFR (93 vs. 67.7 %, P = 0.012) or positive KDR gene (94.4 vs. 47.3 %, P = 0.002). In overall survival time, there was no statistical significance in the two groups ( P = 0.35), in the tumors with positive VEGFR ( P = 0.109) or with positive KDR gene ( P = 0.147). Conclusion: Compared with radiotherapy alone, ES combined with radiotherapy can reduce brain edema in NSCLC patients with BM and obtain better short-term response rate in tumors with positive VEGFR or positive KDR gene, but does not improve the overall survival. [ABSTRACT FROM AUTHOR]

In many patients with brain metastases, the primary therapeutic aim is symptom palliation and maintenance of neurologic function, but in a subgroup, long-term survival is possible. Local control in the brain, and absent or controlled extracranial sites of disease are prerequisites for favorable survival. Stereotactic radiosurgery (SRS) is a focal, highly precise treatment option with a long track record. Its clinical development and implementation by several pioneering institutions eventually rendered possible cooperative group randomized trials. A systematic review of those studies and other landmark studies was undertaken. Most clinicians are aware of the potential benefits of SRS such as a short treatment time, a high probability of treated-lesion control and, when adhering to typical dose/volume recommendations, a low normal tissue complication probability. However, SRS as sole first-line treatment carries a risk of failure in non-treated brain regions, which has resulted in controversy around when to add whole-brain radiotherapy (WBRT). SRS might also be prescribed as salvage treatment in patients relapsing despite previous SRS and/or WBRT. An optimal balance between intracranial control and side effects requires continued research efforts. [ABSTRACT FROM AUTHOR]

Background Large brain metastases (BM) remain a significant cause of morbidity and death for cancer patients despite current advances in multimodality therapies. The goal of the present study was to evaluate the efficacy and limitations of 2-session Gamma Knife stereotactic radiosurgery (SRS) for patients with large BM. Methods This is a prospective, open-label and single arm study analyzing 58 consecutive patients who received 2-session SRS for large BM (⩾ 10 mL). The median age was 66 years, and the median Karnofsky performance status (KPS) score was 70. SRS was the initial treatment in 51 large tumors (84%) and was used as salvage after failed prior treatments for 10 tumors (16%). The fraction protocol was 20-30 Gy given in 2 fractions with 3-4 weeks between fractions. Overall survival (OS) and neurological death (ND), local tumor control and KPS were analyzed. Results The median follow-up time was 9.0 months. One- and 2-year OS rates were 47% and 20%, respectively. The median OS time was 11.8 months (95% CI: 5.5-15.6). The causes of death were intracranial local progression in 5 cases, meningeal carcinomatosis in 3 and progression of the primary lesion in 39. One- and 2-year ND-free survival rates were 91% and 84%, respectively. In 52 of 61 large BM (85%) with sufficient radiological follow-up data, 6- and 12-month local tumor control rates were 85% and 64%, respectively. The mean KPS improved from 70 at the 1st SRS to 82 at the 2nd; the first follow-up mean KPS was 87 (P < 0.001). Symptomatic radiation injury developed and required conservative treatment in 3 patients (5%). Conclusions Long-term follow-up showed that two-session Gamma Knife SRS achieved durable tumor control rates as well as acceptable treatment-related morbidity. This treatment method may potentially merit being offered to patients with large BM who are in poor condition or are otherwise ineligible for standard care. [ABSTRACT FROM AUTHOR]

A second course of whole brain radiation therapy (WBRT) has been employed in selected patients with progressive brain metastases providing favorable symptomatic palliation with acceptable toxicity, although its efficacy and safety remain matter of debate. In the present study we have evaluated the outcomes in patients with progressive intracranial disease treated with WBRT reirradiation and concurrent temozolomide between October 2010 and May 2013. Data were obtained from a prospectively maintained database including patients with brain tumors treated with radiotherapy at Sant'Andrea Hospital. We identified 27 patients (10 males and 17 females) with a median age of 54 years who received WBRT reirradiation at a dose of 25 Gy in ten fractions plus concomitant daily temozolomide administered orally at a dose of 75 mg/m. At the time of repeat WBRT all patients had a KPS ≥ 60. The primary disease sites were lung (n = 18) and breast (n = 9). The median overall survival after the second course of WBRT was 6.2 months and the median time to progression was 5.5 months. Eight patients experienced complete resolution of symptoms, 9 patients had a significant improvement, and 6 patients had no change in their neurologic function. Four patients had further deterioration after reirradiation. Overall, 85 % of patients improved or maintained their neurologic status. No severe acute toxicity during or after the second course of WBRT reirradiation was observed. On multivariate analysis with the Cox proportional hazards model, stable or absent extracranial metastases ( p = 0.005) and response to treatment ( p = 0.01) were independent favorable prognostic factors for survival. The median and 12-month survival rates were 12 months and 50 % in patients with stable or absent extracranial disease and 4.6 months and 7 % in those with progressive extracranial disease ( p = 0.001). In conclusion, in the respect to the small number of treated patients, repeat WBRT plus concomitant temozolomide may be a treatment option in selected patients with multiple brain metastases to improve or maintain neurological conditions and quality of life with acceptable toxicity. The favorable effects of concomitant temozolomide on survival remain unclear. [ABSTRACT FROM AUTHOR]