Initial Diagnosis Of Brain Metastases Research Articles

Selecting Optimal Timing of Cranial Radiotherapy Based on the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA) in Patients with Non-Small Cell Lung Cancer and Brain Metastases

<h3>Purpose/Objective(s)</h3> The updated Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA) index will provide more accurate prediction of expected survival for patients with advanced non-small cell lung cancer (NSCLC) with brain metastases (BM). This retrospective study aims to evaluate optimal timing of cranial radiotherapy (RT) in NSCLC patients with BM stratified by Lung-molGPA index. <h3>Materials/Methods</h3> This study retrospectively screened patients with NSCLC and initially diagnosed BM in our cancer center between February 2012 and July 2018. These enrolled patients were scored and stratified based on lung-molGPA index. The primary endpoint was overall survival time (OS), defined as the interval from the initiation of BM diagnosis to death caused by any reason or the last follow-up. And the secondary endpoint was progression free survival (PFS), referred to the interval from the initiation of BM diagnosis to disease progression or death caused by any reason. The effect of radiotherapy timing on survival time in groups stratified by lung-molGPA index was evaluated. The early RT was defined as receiving RT within three months after initial diagnosis of BM with no progression of BM prior to RT. And the delayed RT was defined as receiving RT after progression of BM or initial diagnosis of BM three months later. <h3>Results</h3> Overall, 471 patients were enrolled in our study, including 260 patients receiving RT. The median follow-up time was 48 months. In entire cohort, median OS time and PFS were 15.0 and 9.0 months, respectively. In lung-molGPA0-2 group, OS of patients with or without RT was no statistical difference (HR, 0.78, 95%CI, 0.59-1.04, P=.071). While in lung-molGPA2.5-4 group, the addition of RT could prolong OS and PFS of patients (OS: HR, 0.51, 95%CI, 0.39-0.67, P<.001; and PFS: HR, 0.66, 95%CI, 0.51-0.85, P<.001). Moreover, in patients scored as 2.5-4.0, the median OS of early RT and delayed RT was 24.0 months and 15.0 months, respectively, and OS of patients receiving early RT was significantly superior to patients receiving delayed RT (HR, 0.50, 95%CI, 0.31-0.79, P<.001). While for patients scored as 0-2, no statistical difference was between OS of patients receiving early RT and delayed RT (HR, 0.75, 95%CI, 0.51-1.10, P=.115). <h3>Conclusion</h3> With regards as patients scored 2.5-4.0 based on lung-molGPA index, early addition of cranial radiotherapy could benefit patients' survival. While for patients scored 0-2, the survival benefit from cranial radiotherapy was limited.

Selecting optimal timing of cranial radiotherapy-based on the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA) in patients with non-small cell lung cancer and brain metastases.

e21105 Background: The updated Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA) index will provide more accurate prediction of expected survival for patients with advanced non-small cell lung cancer (NSCLC) with brain metastases (BM). This retrospective study aims to evaluate optimal timing of cranial radiotherapy (RT) in NSCLC patients with BM stratified by Lung-molGPA index. Methods: This study retrospectively screened patients with NSCLC and initially diagnosed BM in our cancer center between February 2012 and July 2018. These enrolled patients were scored and stratified based on lung-molGPA index. The primary endpoint was overall survival time (OS), defined as the interval from the initiation of BM diagnosis to death caused by any reason or the last follow-up. And the secondary endpoint was progression free survival (PFS), referred to the interval from the initiation of BM diagnosis to disease progression or death caused by any reason. The effect of radiotherapy timing on survival time in groups stratified by lung-molGPA index was evaluated. The early RT was defined as receiving RT within three months after initial diagnosis of BM with no progression of BM prior to RT. And the delayed RT was defined as receiving RT after progression of BM or initial diagnosis of BM three months later. Results: Overall, 471 patients were enrolled in our study, including 260 patients receiving RT. The median follow-up time was 48 months. In entire cohort, median OS time and PFS were 15.0 and 9.0 months, respectively. In lung-molGPA0-2 group, OS of patients with or without RT was no statistical difference (HR, 0.78, 95%CI, 0.59-1.04, P= .071). While in lung-molGPA2.5-4 group, the addition of RT could prolong OS and PFS of patients (OS: HR, 0.51, 95%CI, 0.39-0.67, P&lt; .001; and PFS: HR, 0.66, 95%CI, 0.51-0.85, P&lt; .001). Moreover, in patients scored as 2.5-4.0, the median OS of early RT and delayed RT was 24.0 months and 15.0 months, respectively, and OS of patients receiving early RT was significantly superior to patients receiving delayed RT (HR, 0.50, 95%CI, 0.31-0.79, P&lt; .001). While for patients scored as 0-2, no statistical difference was between OS of patients receiving early RT and delayed RT (HR, 0.75, 95%CI, 0.51-1.10, P= .115). Conclusions: With regards as patients scored 2.5-4.0 based on lung-molGPA index, early addition of cranial radiotherapy could benefit patients’ survival. While for patients scored 0-2, the survival benefit from cranial radiotherapy was limited.

Hippocampal Metastasis Rate Based on Non-Small Lung Cancer TNM Stage and Molecular Markers.

Hippocampal-avoidance whole-brain radiation therapy (HA-WBRT) is justified because of low hippocampal brain metastases (BM) rate and its prevention of cognitive decline. However, we hypothesize that the risk of developing BM in the hippocampal-avoidance region (HAR) may differ depending on the lung-cancer stage and molecular status. We retrospectively reviewed 123 patients with non-small cell lung cancer (NSCLC) at the initial diagnosis of BM. The number of BMs within the HAR (5 mm expansion) was counted. The cohort was divided into patients with and without BMs in the HAR, and their clinical variables, TNM stage, and epidermal growth factor receptor (EGFR) status were compared. The most influential variable predicting BMs in the HAR was determined using multi-variable logistic regression, classification and regression tree (CART) analyses, and gradient boosting method (GBM). The feasibility of HAR expansion was tested using generalized estimating equation marginal model. Patients with BMs in the HAR were more frequently non-smokers, and more likely to have extra-cranial metastases and EGFR mutations (p<0.05). Multi-variable analysis revealed that extra-cranial metastases were independently associated with the presence of BM in the HAR (odds ratio=8.75, p=0.04). CART analysis and GBM revealed that the existence of extra-cranial metastasis was the most influential variable predicting BM occurrence in the HAR (variable importance: 23% and relative influence: 37.38). The estmated BM incidence of patients without extra-cranial metastases in th extended HAR (7.5-mm and 10-mm expansion) did not differ significantly from that in the conventional HAR. In conclusion, NSCLC patients with extra-cranial metastases were more likely to have BMs in the HAR than those without extra-cranial metastases.

Abstract PO-219: Examining racial differences in tumor growth rates for metastatic breast cancer to the brain

Abstract INTRODUCTION: Breast cancer is a common cause of brain metastases, occurring in at least 10–16 % of patients. Unfortunately, patients who develop brain metastases tend to have a poor prognosis with short overall survival. Moreover, for reasons we do not fully understand, African American women tend to have a worse prognosis and survival rate of about only 17% after 2 years of initial diagnosis of brain metastases. Our hypothesis in this project is that brain metastases in African American patients will have a higher growth rate compared to their white counterparts and that this may partially explain the worse prognosis for this population. However, measurement of growth rates of metastatic brain cancer has not been performed previously. A secondary objective is to test whether a combination of repeat brain MRI scans and dedicated software for automatic tumor sizing can be used to determine growth rates of individual brain lesions in this patient population and statistically correlate these with race and primary tumor type. METHODS: This was a pilot retrospective study of women who had been diagnosed with primary breast cancer that metastasized to the brain where multiple follow-up brain MRI scans were available. We used in-house software built upon the NIH ImageJ package to detect and accurately size nodules from the T1-weighted, post-contrast brain MRI scans[RA ref]. Patient factors of age, race, and primary tumor type we gathered as well as the type of treatment: surgery, chemotherapy, whole-brain radiation therapy, and/or stereotactic radiosurgery. RESULTS: To-date we have analyzed the growth rates of 20 brain metastases in 6 women: 3 Blacks, 3 Whites, 3 with ER+, 3 with ER- primary tumors, and age range 31-86 years. We have still not received sufficient results from our computational studies but will be getting soon. CONCLUSION: We have demonstrated the measurement of growth rates of individual brain metastases using repeated post-contrast brain MRIs and dedicated image analysis software. We have successfully applied these in 10 tumors from 20 breast cancer patients with known metastases to the brain. We have shown that growth rates differ between racial and ER+/- cohorts but additional datasets are needed to establish a statistical correlation. We hope these initial results motivate larger future studies that can investigate the role in breast cancer outcomes of patient and societal factors such as race, age, presence of comorbidities, primary tumor type, the aggressiveness of initial treatment, access to medical care, and socioeconomic factors. Citation Format: Daniel Sola, Jada Harvey, Walter O'Dell. Examining racial differences in tumor growth rates for metastatic breast cancer to the brain [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-219.

Risk of Intracerebral Hemorrhage with and without Anticoagulation in Patients with Brain Metastasis: The Cleveland Clinic Experience

Background: Venous thromboembolism (VTE) occurs frequently in cancer patients and is commonly treated with therapeutic anticoagulation. Treatment of VTE in cancer patients with brain metastasis is an area of concern due to known risk of intracerebral hemorrhage (ICH). We evaluated risk of ICH in cancer patients with known brain metastases with or without anticoagulation. Methods: Cancer patients diagnosed with brain metastasis between 12/2005 and 7/2018 were identified using a radiation oncology database and electronic records were retrospectively reviewed. Patients with primary brain tumors and absence of follow-up brain imaging were excluded. Clinically significant ICH was defined as ICH resulting in focal neurologic deficit or requiring neurosurgery. Overall survival (OS) calculated from initial diagnosis of brain metastasis, estimated by the Kaplan-Meier method, and compared by the log-rank test. Predictors identified as statistically significant on univariate logistic regression analysis (p&amp;lt;0.05) were selected for multivariate analysis. Results: We identified 903 cancer patients with brain metastasis. Of these, 629 (69.7%) met inclusion criteria. Among all included patients, 130 (20.7%) received therapeutic anticoagulation (AC) [enoxaparin: n = 75 (57.7%), warfarin: n = 41 (31.5%), apixaban/rivaroxaban/fondaparinux: n = 7 (5.4%), and unfractionated heparin: n = 7 (5.4%)] due to VTE after diagnosis of brain metastasis, 499 (79.3%) patients did not receive AC. Patient baseline and treatment characteristics for both cohorts are shown in Table 1. Deep vein thrombosis and pulmonary emboli were identified in 133 (21.1%) and 77 (12.2%) patients respectively. ICH was recorded in 130 (20.7%) patients at the time of brain metastasis diagnosis. In the AC cohort, 22 of 130 (16.9%) patients had ICH, of which 13 (59.1%) clinically significant and 9 (40.9%) clinically insignificant at the time of brain metastasis diagnosis. In the no-AC cohort, 108 of 499 (21.6%) patients had ICH, of which 79 (73.1%) clinically insignificant and 29 (26.9%) clinically significant at the time of brain metastasis diagnosis. Median follow-up time of patients was 8.2 months. During the follow up time, ICH was detected in 14 (2.2%) patients overall, 12 (85.7%) patients were in the AC group and the other two (14.3) patients were in the no-AC group. Ten (71.4%) patients had clinically significant ICH. In univariable analysis, male gender [p = 0.001] and primary cancer subtype (melanoma and renal cell cancer vs others) [p = &amp;lt;.001] were predictors of ICH at the time of brain metastasis diagnosis. In multivariable analysis, both gender and primary malignancy subtype [p &amp;lt;0.001 and .007 respectively] remained statistically significant predictors of ICH at the time of brain metastasis diagnosis (Table 2). In multivariate analysis, only number of brain lesions was a predictor of clinically significant ICH at the time of brain metastasis diagnosis [p=.036]. In multivariate analysis, ICH at diagnosis, therapeutic ACs use, type of ACs, and duration of ACs were significant predictors of ICH after brain metastasis diagnosis [all p &amp;lt;.0001]. None of the patients who had ICH received heparin, 42.9% received warfarin, 35.7% received enoxaparin, and 7.1% received direct oral anticoagulant (DOACs) [p &amp;lt;.0001]. One-year OS of patients with brain metastasis who received anticoagulation and did not receive anticoagulation was 44% (95% CI: 36 - 54) and 49% (95% CI: 44 -54), respectively (p=0.5) (Figure 1A). One year OS of patients with brain metastasis who had ICH and did not have ICH was 42% (95% CI: 33 - 52) and 49% (95% CI: 45 - 54), respectively (p=0.05) (Figure 1B). Conclusion: In this cohort study, melanoma, renal cell cancer and male gender were significantly associated with increased risk of ICH. The use of therapeutic anticoagulation and history of ICH were associated with a greater risk of clinically significant ICH without affecting overall survival. About 88% of patients who had ICH during the follow up period received either warfarin or enoxparin. Larger studies are needed to better understand the safety profile of DOACs in this setting. Disclosures Khorana: Janssen: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy.

Acute neurological adverse events during immune checkpoint inhibition therapy in patients with melanoma brain metastases.

The common adverse effects of immune checkpoint blockade therapy are well recognised. However, neurological adverse effects of checkpoint inhibitor therapy are less widely appreciated, and their clinical management remains challenging. Therefore, we report our experience of managing acute, life-threatening neurological toxicity during immune checkpoint inhibitor therapy. Five male patients with stage IV melanoma underwent anti-programmed cell death protein 1 therapy (monotherapy or combination therapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies) and developed severe neurological symptoms and signs including headache, hemiparesis and dysarthria. The initial diagnosis of brain metastases actually occurred after initiation of checkpoint inhibitor therapy in three of the patients, whereas two patients had pre-existing central nervous metastases and developed cerebral oedema and haemorrhage during immunotherapy. A rapidly fatal outcome occurred in two patients treated with immunotherapy following the development of BRAF-inhibitor and MEK-inhibitor resistance. Four of the patients died owing to neurological complications, and one achieved a complete cerebral response. Immunotherapy and tumour progression can both result in the development of neurological symptoms and signs, making it difficult to determine causality. However, the temporal relationship between the development of neurological symptoms and the first administration of therapy means that patients should be closely monitored for the development of neurological sequelae, which may even herald the presence of occult brain metastases. The decision on whether to continue immunotherapy must balance the risks of symptom - versus disease progression. However, in our case series, it is encouraging to note that the initial acute neurological symptoms were often transient. Nevertheless, pretherapeutic brain imaging to exclude occult brain metastases and stratify the risk of intracerebral oedema and haemorrhage should be considered.

Survival Impact of Optimal Surgical Cytoreduction in Recurrent Epithelial Ovarian Cancer with Brain Metastasis

Aim: The aim of this study was to determine the clinicopathological characteristics, treatment details and outcome of patients with brain metastasis from epithelial ovarian carcinoma (EOC). Methods: This study included 21 patients diagnosed with brain metastasis from EOC between 1999 and 2009. Results: Median age was 61 years (range 38-77). The median time elapsed from EOC diagnosis to brain metastasis detection was 32 months. Single brain metastases were found in 10 (48%) cases, and there was extra-cranial disease in 11 (52%) cases. During the mean 86 months of follow-up, 18 of the patients (86%) died of the disease and 3 (14%) were alive with disease. The median survival time after the initial diagnosis of brain metastasis was 9 months. The median overall survival (OS) from initial diagnosis of EOC was 50 months. In univariate analysis, prolonged time from initial diagnosis to central nervous system metastasis (more than 32 months) (p = 0.001), treatment with radiotherapy (p < 0.001), optimal cytoreductive operation (p = 0.02) were all positively correlated with OS. Conclusion: The prognosis of patients with brain metastasis from EOC is still poor. The significant predictors of survival in our series were whole brain radiotherapy, prolonged elapsed time from initial diagnosis to brain metastasis and optimal cytoreductive surgery.

Outcomes Associated with Therapeutic Anticoagulation in Patients with Brain Metastasis

Background:Venous thromboembolism (VTE) is a highly prevalent complication of cancer and its treatment and is commonly treated with anticoagulation1. However, there are limited data regarding the use of therapeutic anticoagulation in patients with brain metastases, due to concerns for intracranial hemorrhage (ICH).Methods:We retrospectively identified cancer patients who were diagnosed with brain metastasis between 12/2005 and 7/2017, and subsequently underwent whole brain radiation at the Cleveland Clinic. Patients with primary brain tumors, leptomeningeal disease alone, and absence of follow-up brain imaging were excluded. Clinically significant ICH was defined as ICH resulting in focal neurologic deficit or required neurosurgery, as previously described2. Cumulative incidence of ICH from initial diagnosis of brain metastasis was calculated with death as competing risk. Difference between cumulative incidence estimates was tested using Gray's test. Overall survival (OS) calculated from initial diagnosis of brain metastasis, estimated by the Kaplan-Meier method, and compared by the log-rank test. Median follow-up time was calculated using reverse Kaplan-Meier method. Predictors identified as statistically significant on univariate logistic regression analysis (p<0.05) were selected for multivariate analysis.Results:We screened568 patients and identified 407 who meet inclusion criteria. Seventy-eight (19%) patients received therapeutic anticoagulation (AC) [enoxaparin: n = 46 (59%), warfarin: n = 27 (35%), apixaban/rivaroxaban: n = 3 (4%), unfractionated heparin: n = 2 (2%)] due to VTE after diagnosis of brain metastasis, whereas 329 (81%) patients did not receive any therapeutic dose of AC. There were more female patients in the AC cohort, but other baseline characteristics were similar in both cohorts (Table 1).In the AC cohort, 11 of 78 (14%) patients had ICH, of which 6 (55%) were clinically insignificant and 5 (45%) were clinically significant at initial diagnosis of brain metastasis. Five of 11 patients were already on AC before diagnosis of brain metastasis. In the no-AC cohort, 65 of 329 (20%) patients had ICH, of which 53 (82%) clinically insignificant and 12 (18%) clinically significant at initial diagnosis of brain metastasis. Median follow-up of patients was 28 months. The 3-year cumulative incidence of clinically insignificant ICH in AC and no-AC groups was 7.7 (95% CI: 1.8 - 13.6) and 21.3 (95% CI: 16.5 - 26.1), respectively (p = 0.017). The 3-year cumulative incidence of clinically significant ICH in AC and no-AC groups was 12.0 (95% CI: 4.6 - 19.4) and 4.9 (95% CI: 2.6 - 7.4), respectively (p = 0.044). The 3-year cumulative incidence of all ICH in AC and no-AC groups was 19.7 (95% CI: 10.7 - 28.7) and 25.8 (95% CI: 20.9 - 30.7), respectively (p = 0.27). The 3-year OS in AC and no-AC groups was 13.6 (95% CI: 6.9 - 26.4) and 17.6 (95% CI: 12.9 - 23.9), respectively (p = 0.64) (Figure 1).In univariable analysis, AC vs no-AC [OR: 2.39, 95% CI: 1.00 - 5.48, p = 0.044] and primary cancer (melanoma vs lung) [OR: 5.62, 95% CI: 1.78 - 16.49, p = 0.002] were predictors of clinically significant ICH after diagnosis of brain metastasis (Table 2). In multivariable analysis, only primary cancer (melanoma vs lung) [OR: 6.19, 95% CI: 1.92 - 18.88, p = 0.001]remained a statistically significant predictor of clinically significant ICH after diagnosis of brain metastasis.Conclusion:In this relatively large cohort of patients with brain metastasis, use of therapeutic anticoagulation did not influence the incidence of developing ICH but was associated with a greater risk of clinically significant ICH. This increase was, however, not linked to differences in overall survival. Nearly all patients in our AC cohort were treated with enoxaparin; ongoing studies will examine whether anticoagulation with DOACs is associated with similar outcomes. [Display omitted] DisclosuresKhorana:Bayer: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Pfizer: Consultancy.

Radiological distribution of brain metastases and its implication for the hippocampus avoidance in whole brain radiotherapy approach.

Hippocampus avoidance in whole brain radiotherapy (HA-WBRT) offers the feasibility of less-impaired cognitive function than conventional WBRT. The study aims to assess the radiological distribution of brain metastases (BMs) with relation to the hippocampus and peri-hippocampus region as defined by the RTOG 0933 for better understanding of margin definition in HA-WBRT treatment planning. Consecutive patients with diagnosis of BM from enhanced MRI between March 2011 and July 2016 were analysed. The pre-treatment T1 weighted, T2 weighted, T2 flair, three-dimensional spoiled gradient axial and contrast-enhanced axial cranial MR images of 226 patients are examined. The closest distances between the edge of hippocampus and the margin of tumours on different planes were measured. A total of 226 patients with 1080 visible metastatic sites were reviewed. The origin of the primary tumors was in 72.6% lung (n = 164), in 45 cases (19.9%) breast cancer and in 7.5% other malignancies (n = 17). There were 758 (70.2%) lesions situated beyond the tentorium. The median size of single lesion was 13.9 ± 14.7 mm. Impossible, it seems that more of the patients are with only one lesion, to verify. The hippocampus involvement was found in 3.1% (n = 7, 95% CI 0.01-0.05) within 5 mm, 5.7% (n = 13, 95% CI 0.03-0.09) within 10mm and 8.4% (n = 19, 95% CI 0.05-0.12) within 20 mm. In multivariate analysis, the number 6 BM or higher was found to be an independent risk factor for hippocampal involvement (HI) (OR: 5.2, 5.38 and 3.84 in 5, 10 and 20 mm). This radiological study found that the incidence of hippocampus involvement is low in patients with BM. HA-WBRT can be delivered under the context of complete radiological diagnosis after careful delineation, proper margin definition and individual planning optimization. Advances in knowledge: The incidence of HI in patients with initial diagnosis of BM from solid tumours impacts the radiotherapeutic decision. Our radiological data analysed the incidence of HI not only to the conventional 5 mm margin definition, but also expanded to wider margins as 10 and 20 mm from hippocampus, which will help the treatment planning optimization with different technique.

Correlation between characteristics of intracranial lesions and level of cognitive function in patients with an initial diagnosis of brain metastases

Objective To investigate the correlation between the characteristics of intracranial lesions and the level of cognitive function in patients with an initial diagnosis of brain metastases. Methods A retrospective analysis was performed in 51 patients with an initial diagnosis of brain metastases who were admitted to The Second Hospital Affiliated to Suzhou University from January 2015 to April 2016.CT and (or) MRI were used to determine the characteristics of intracranial lesions and the Montreal Cognitive Assessment was used to evaluate the cognitive function of patients. Comparison between groups was made by Mann-Whitney U test. The correlation between ranked data was analyzed by Spearman rank correlation test. Results Of the 51 patients with an initial diagnosis of brain metastases, 47(92%) had cognitive impairment, including mild cognitive impairment in 31(61%) and dementia in 16(31%). There was no significant difference in level of cognitive function between the patients with involvement of the left hemisphere alone and those with involvement of the right hemisphere alone (P=0.425). The patients with involvement of both hemispheres had a significantly lower level of cognitive function than those with involvement of the left hemisphere alone (P=0.042). The patients with involvement of three or more brain lobes had a significantly lower level of cognitive function than those with involvement of one or two brain lobes (P=0.015, 0.024). The intracranial lesion volume and edema volume had no significant effect on the overall cognitive function of patients (P=0.077, 0.178). The patients with>3 intracranial lesions had a significantly lower level of cognitive function than those with 1-3 intracranial lesions (P=0.010). Conclusions More than 90% of patients with an initial diagnosis of brain metastases have cognitive impairment. Cognitive impairment is mainly associated with lesion site, involvement of brain lobes, and number of lesions, but not with lesion volume and edema volume. Key words: Neoplasms metastases, brain; Cognitive function; Cognitive assessment

Clinical and Radiographic Outcomes From Repeat Whole-brain Radiation Therapy for Brain Metastases in the Age of Stereotactic Radiosurgery

Repeating whole-brain radiation therapy (WBRT) in patients with progressive/recurrent brain metastases is controversial. We retrospectively reviewed our experience of repeat WBRT in an era where stereotactic radiosurgery was also available. In our IRB-approved database, 49 patients received repeat WBRT from 1996 to 2011. Median initial dose of WBRT was 30 Gy in 10 fractions (range, 27 to 37.5 Gy); median reirradiation dose was 20 Gy in 10 fractions (range, 14 to 30 Gy). Median Karnofsky performance status (KPS) at reirradiation was 70 (range, 40 to 90). Median number of discrete lesions at reirradiation was 6 (range, 1 to 30). Median interval between initial diagnosis of brain metastases and relapse requiring repeat WBRT was 11.5 months (range, 1.5 to 49.2 mo). Overall survival and relapse-free survival were summarized using the Kaplan-Meier method. The log-rank test was used to compare outcomes between groups. Ninety percent of patients completed repeat WBRT. Median survival after repeat WBRT was 3 months (95% CI, 1.9-4.0). Thirteen patients had improved neurological symptoms (27%), 12 were stable (24%), and 14 had worsening symptoms (29%). On radiographic follow-up of 22 patients, 10 (46%) were improved, 4 (18%) were stable, and 8 (36%) progressed. Improved neurological symptoms after repeat WBRT and higher KPS at first follow-up were associated with improved survival (P=0.05 and 0.02). Repeat WBRT was well tolerated. Modest survival times are seen. Prognostic factors for survival include improved neurological symptoms after repeat WBRT and higher KPS at first follow-up. Repeat WBRT may be useful to improve neurological symptoms in patients with limited treatment options, especially those who are not appropriate stereotactic radiosurgery candidates.

Capacity of patients with brain metastases to make treatment decisions.

The aim of this study was to investigate medical decision-making capacity (MDC) in patients with brain metastases. Participants were 41 adults with brain metastases with Karnofsky Performance Status scores of ≥70 who were recruited from an academic medical center and 41 demographically matched controls recruited from the community. We evaluated MDC using the Capacity to Consent to Treatment Instrument and its four clinically relevant consent standards (expressing a treatment choice, appreciation, reasoning, and understanding). Capacity impairment ratings (no impairment, mild/moderate impairment, and severe impairment) on the consent standards were also assigned to each participant with brain metastasis using cutoff scores derived statistically from the performance of the control group. The brain metastasis patient group performed significantly below controls on consent standards of understanding and reasoning. Capacity compromise was defined as performance ≤1.5 standard deviations below the control group mean. Using this definition, approximately 60% of the participants with brain metastases demonstrated capacity compromise on at least one MDC standard. When defining capacity compromise as performance ≤1.5 standard deviation below the control group mean, over half of patients with brain metastases have reduced capacity to make treatment decisions. This impairment is demonstrated shortly after initial diagnosis of brain metastases and highlights the importance of routine clinical assessment of MDC following diagnosis of brain metastasis. These results also indicate a need for the development and investigation of interventions to support or improve MDC in this patient population.

Repeat Whole Brain Radiation Therapy with a Simultaneous Infield Boost: A Novel Technique for Reirradiation

The treatment of patients who experience intracranial progression after whole brain radiation therapy (WBRT) is a clinical challenge. Novel radiation therapy delivery technologies are being applied with the objective of improving tumor and symptom control in these patients. The purpose of this study is to describe the clinical outcomes of the application of a novel technology to deliver repeat WBRT with volume modulated arc therapy (VMAT) and a simultaneous infield boost (WB-SIB) to gross disease. A total of 16 patients were initially treated with WBRT between 2000 and 2008 and then experienced intracranial progression, were treated using repeat WB-SIB, and were analyzed. The median dose for the first course of WBRT was 35 Gy (range: 30–50.4 Gy). Median time between the initial course of WBRT and repeat WB-SIB was 11.3 months. The median dose at reirradiation was 20 Gy to the whole brain with a median boost dose of 30 Gy to gross disease. A total of 2 patients demonstrated radiographic disease progression after treatment. The median overall survival (OS) time from initial diagnosis of brain metastases was 18.9 months (range: 7.1–66.6 (95% CI: 0.8–36.9)). The median OS time after initiation of reirradiation for all patients was 2.7 months (range: 0.46–14.46 (95% CI: 1.3–8.7)). Only 3 patients experienced CTCAE grade 3 fatigue. No other patients experienced any ≥ CTCAE grade 3 toxicity. This analysis reports the result of a novel RT delivery technique for the treatment of patients with recurrent brain metastases. Side effects were manageable and comparable to other conventional repeat WBRT series. Repeat WB-SIB using the VMAT RT delivery technology is feasible and appears to have acceptable short-term acute toxicity. These results may provide a foundation for further exploration of the WB-SIB technique for repeat WBRT in future prospective clinical trials.

Control of brain metastases for HER2-positive breast cancer with bevacizumab: a report of three patients

Introduction: Brain metastases are diagnosed in approximately 6% to 16% of all metastatic breast cancer patients. Theincidence of brain metastases is much higher for patients with human epidermal growth factor receptor 2 (HER2)-positivebreast cancers, in the range of 25% to 34%. More patients are presenting with uncontrolled brain metastases sincetrastuzumab-based therapy has improved survival in this population. However, treatment options in these patients arelimited after whole brain radiation therapy (WBRT) has failed. Case presentation: In an effort to control brain metastases, three patients who had progression of HER2-positive breastcancer after WBRT received the angiogenesis-inhibiting drug bevacizumab, a humanized monoclonal antibody against thevascular endothelial growth factor (VEGF) ligand. The patients showed clinical improvement and regression of tumorgrowth. After initial diagnosis of brain metastases, patient 1 survived 14 months, patient 2 survived 32 months, and patient3 survived 45 months. Bevacizumab controlled brain metastases for 6, 13, and 19 months, respectively, after progressionon WBRT. Conclusion: This subset of patients with brain metastases and HER2/neu-positive breast cancer clearly responded to ananti-VEGF regimen, suggesting the need for a prospective clinical trial of bevacizumab with lapatinib or otherHER2-targeted therapy in this patient group.

Management of brain metastases from ovarian and endometrial carcinoma with stereotactic radiosurgery

Metastases to the brain from ovarian and endometrial carcinoma are uncommon and to the authors' knowledge consensus regarding optimal management is lacking. Stereotactic radiosurgery (SRS) has proven useful for the treatment of many benign and malignant brain tumors. In the current study, the authors evaluated outcomes after SRS in patients with ovarian and endometrial carcinoma. Twenty-seven patients with brain metastases underwent gamma-knife SRS. Six patients had endometrial carcinoma, whereas 21 patients had ovarian carcinoma. Eighteen patients also received whole-brain radiotherapy. A total of 68 tumors were treated with gamma-knife SRS. At the time of last follow-up, 1 patient was still alive and 26 had died. The median survival was 7 months after the initial diagnosis of brain metastasis and 5 months after SRS. The 1-year survival rate after radiosurgery was 15% and that from the diagnosis of brain metastases was 22%. On final imaging, all tumors were controlled without further growth. Two patients (7.4%) developed new or progressive neurologic deficits after SRS. SRS is an acceptable choice for the treatment of brain metastases resulting from ovarian and endometrial carcinoma, and provides local tumor control with limited morbidity. Careful patient selection is warranted in the setting of patients with uncontrolled systemic disease in whom a limited survival benefit is expected.

Salvage stereotactic radiosurgery effectively treats recurrences from whole‐brain radiation therapy

The purpose of the current study was to examine overall survival (OS) and time to local failure (LF) in patients who received salvage stereotactic radiosurgery (SRS) for recurrent brain metastases (BM) after initial management that included whole-brain radiation therapy (WBRT). The records of 1789 BM patients from August 1989 to November 2004 were reviewed. Of these, 111 underwent WBRT as part of their initial management and SRS as salvage. Patients were stratified by Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis class, primary disease, dimension of the largest metastases and number of BM at initial diagnosis, and time to first brain recurrence after WBRT. Overall survival, survival after SRS, and time to local and distant failure were analyzed. The median OS from the initial diagnosis of BM was 17.7 months. Median survival after salvage SRS for the entire cohort was 9.9 months. Median survival after salvage SRS was 12.3 months in patients who had their first recurrence >6 months after WBRT versus 6.8 months for those who developed disease recurrence < or = 6 months after (P = .0061). Primary tumor site did not appear to affect survival after SRS. Twenty-eight patients (25%) developed local recurrence after their first SRS with a median time of 5.2 months. A dose <22 grays and lesion size >2 cm were found to be predictive of local failure. In this study, patients who recurred after WBRT and were treated with salvage SRS were found to have good local control and survival after SRS. WBRT provided good initial control, as 45% of these patients failed >6 months after WBRT. Those with a longer time to failure after WBRT had significantly longer survival after SRS.

HER2-neu status as a predictor of survival in patients with brain metastases from primary breast adenocarcinoma

1016 Background: Recent data suggests that Her2-neu positivity predicts for development of brain metastases in patients with breast cancer. However, there now exists a targeted agent, trastuzumab, that provides excellent systemic control of Her2-positive (Her2 +) disease. We therefore explore the course of this disease as a function of Her2 status in patients with primary breast cancer who have developed brain metastases. Method: We retrospectively analyzed data from 50 consecutive patients with primary breast cancer who subsequently developed brain metastases. Factors evaluated included Her2-neu, ER/PR, T stage, nodal stage, use of whole brain radiotherapy (WBRT) as initial management of CNS disease, initial number of metastases, hormonal therapy, use of trastuzumab, and Karnofsky Performance Status (KPS). Overall survival (OS) was modeled using Cox proportional hazard. Kaplan-Meier analysis was used for significant predictors. Results: Median age was 49 years (28–78 y). Fifty-four percent of patients were Her2 +, whereas only 15% were ER +. All but one Her2 + patient received trastuzumab. Seventy-two percent were node positive, and only 5 patients were metastatic at time of diagnosis. T stage was as follows: T1 = 24%, T2 = 36%, T3 = 8%, and T4 = 16%. Adjuvant chemotherapy was administered to 90% of the sample, and 94% underwent radiation to the primary site. Sixty-six percent had &lt;= 3 initial brain metastases, and 38% underwent WBRT as part of their initial CNS management. Median followup was 55 weeks. A Cox multivariate model of OS yielded two independent predictors. Her2 positivity (p = 0.007) and &lt;= 3 initial brain metastases (p = 0.003) were associated independently with OS from time of initial diagnosis of CNS disease. Median survival and actuarial one year survival for Her2 + patients were 65 weeks and 87%, respectively, versus 33 weeks and 44% for Her2 negative patients (Mantel Cox p = 0.025). Conclusions: Although Her2 + patients appear to have a greater risk of developing brain metastases, overall survival from time of initial diagnosis of brain metastasis appears to be better in this cohort. This may be a function of the improved extracranial control provided by trastuzumab in patients with Her2+ disease. No significant financial relationships to disclose.