Search

Classical leptomeningeal disease (cLMD) has historically been considered a global phenomenon impacting the entire craniospinal axis, but isolated parenchymal metastases sometimes display focal leptomeningeal extension into the surrounding leptomeninges without diffuse LMD elsewhere. Descriptions of this phenomenon are lacking, and the optimal management of such patients remains unclear. We hypothesized that, in order to spare such patients the deleterious outcomes of whole brain radiation (WBRT), patients with focal LMD (fLMD) could be successfully managed with stereotactic radiation (SRS/SRT) without excess development of adverse sequelae such marginal recurrences or subsequent cLMD. We identified 796 patients with 2,354 newly-diagnosed brain metastases (BrM) secondary to a solid tumor primary without cLMD at diagnosis managed at a tertiary cancer center between 2007-2022. Each metastasis was assessed for fLMD, which was defined as isolated focal leptomeningeal extension of an intact brain metastasis or single, isolated focal leptomeningeal enhancement without cytologic or radiographic evidence of cLMD (enhancement of cranial nerves or multifocal involvement of subarachnoid spaces including the cerebellar folia and supratentorial sulci). Multivariable Fine and Gray's models were constructed for the primary outcomes of local recurrence and development of cLMD. Among 796 patients, 138 (17.3%) displayed evidence of fLMD, corresponding to 185 of 2,354 (7.9%) BrM. Patients with versus without fLMD were not more likely to display distant intracranial failures post-initial treatment (56.8% vs. 58.3% at 1 year, respectively, p=0.78) or local recurrence (4.4% vs. 8.2% at 1 year, respectively, p=0.14), including in lesions managed with SRS/SRT (1-year local recurrence: 4.4% vs. 4.9%, respectively; p=0.63). On a per-patient level, the presence of fLMD was not a significant predictor of development of cLMD (1-year rate: 5.2% vs 5.2%, HR: 0.99 [0.52-1.89], p=0.97). We describe a novel pattern of LMD that has not been well-characterized in prior literature; fLMD appears to be a distinct oncologic entity whose pattern of intracranial failure resembles that of parenchymal BrM. Nationally, it may be that patients with fLMD are managed as having cLMD with routine use of WBRT. Our study suggests that despite the presence of enhancing disease in the leptomeningeal space, stereotactic approaches may be viable in this population given the lack of detectable excess risk of local recurrence or development of cLMD. [ABSTRACT FROM AUTHOR]

Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. As a result, radiation doses and fractionation schemes are relatively homogeneous and prescribed with a "one-size-fits-all" approach. We hypothesized that tumor-specific genomic alterations may underlie radiation sensitivity among patients with BrM and sought to develop a DNA-based signature of radiation-based efficacy in this patient population, utilizing genes that are readily testable in modern-day assays, to identify subpopulations at greater vs. lesser risk of recurrence. We identified 570 patients with 1,487 distinct BrM managed with whole-brain (WBRT) or stereotactic radiation therapy (SRS/SRT) at a tertiary cancer center (2013-2020) for whom next-generation sequencing panel data (OncoPanel, 239 genes) were available on at least one extracranial or intracranial tumor specimen. Fine/Gray's competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with vs. without somatic alterations of likely biological significance across 84 OncoPanel genes with a mutational frequency of > 0.5%. Genes with a q-value < 0.10 were utilized to develop a numeric "Brain-Radiation Prediction Score" ("Brain-RPS") to quantify local recurrence risk. Genomic alterations of potential biological relevance in 11 (ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, MDM4) and two genes (FBXW7 and AURKA) were associated with a decreased or increased risk of local recurrence, respectively (q-value < 0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level Brain-RPS. On multivariable Fine/Gray's competing risks regression, Brain-RPS [1.66 (1.44-1.92, p<0.001)], metastasis-associated edema [1.89 (1.38-2.59), p<0.001], and receipt of WBRT without SRS/SRT or neurosurgical resection [2.73 (1.78-4.20), p<0.001] were independent predictors of local failure. Utilizing a targeted panel of genes with a known role in cancer pathogenesis, we developed a genomic score that can be calculated from an extracranial or intracranial site to quantify local recurrence risk following brain-directed radiation. Prior attempts to develop a biomarker-based radiation response signature have not focused on patients with BrM and have primarily relied on RNA-based measures of radiosensitivity, limiting their utility in real-world clinical practice for this patient population. To our knowledge, this represents the first study to systemically correlate DNA-based alterations with radiation-based outcomes among patients with BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genome-based personalization of radiation treatment among patients with BrM. [ABSTRACT FROM AUTHOR]

Brain metastases (BrM) commonly affect patients with solid malignancies and often correlate with significant symptomatology that profoundly impacts patients' quality of life (QOL). As systemic therapies increasingly improve extracranial disease control but lag in intracranial efficacy, a rising incidence of BrM persists. Thus, an urgent need exists to characterize the most common symptoms associated with BrM and to correlate these symptoms with survival. We identified patients who received radiation therapy (RT) within 30 days of BrM diagnosis at a tertiary cancer center between 2017-2020 who prospectively completed the MD Anderson Symptom Instrument-Brain Tumor questionnaire (a validated instrument among patients with BrM for evaluation of 22 symptoms and 6 interference measures linked to daily functioning). Symptom severity score (range 0-10, with higher scores indicating more severe symptomatology) and interference score (range 0-10, with higher scores indicating greater compromise of activity-related/affective function), were compared via t-test or ANOVA by: age (>65 vs. ≤65), sex, Karnofsky performance status (KPS) (high, 90-100 vs. low, <90), Charlson co-morbidity index (CCI) (high, >2 vs. low, 0-2), primary tumor type (lung, breast, melanoma, other), and initial intracranial treatment strategy (surgical resection, stereotactic RT, or whole brain RT). Overall survival (OS) was assessed via Cox regression with the above co-variates; symptom severity and interference were evaluated in separate Cox models. A total of 101 patients were identified (median age=67 years, female=60%, primary lung cancer=45%). Mean symptom severity and interference scores at time of BrM diagnosis were 2.4 and 3.4, respectively. The most common severe (defined as a score >4) symptoms were: fatigue (47%), distress (40%), sleep disturbances (37%), drowsiness (35%), and sadness (32%). The most common high (score>4) interference measures were: enjoyment of life (47%), ability to work (44%), and walking (35%). Higher symptom severity was more common among females than males (2.8 vs 1.8, respectively; p=0.01); there were no significant differences in mean symptom severity or interference scores by age, KPS, CCI, or initial BrM treatment strategy. On Cox regression, higher symptom severity and higher interference scores were associated with worse OS (HR 1.30 per 1-point increase [95% CI, 1.11-1.51], p<0.001; and HR 1.18 per 1-point increase [95% CI 1.07-1.30], p=0.001, respectively); age, KPS, CCI, and other co-variates were not significantly associated with OS. High symptom and interference burden is common among patients with BrM and associated with worse survival. Further work should investigate how improving symptoms, such as through palliative care interventions, may impact QOL trajectories and survival among the BrM patient population. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): The prognosis for patients with brain metastases (BrM) remains guarded, with population-based data indicating a median survival of 3-12 months. However, a subset of patients with BrM display prolonged survival. We sought to characterize the likelihood and predictors associated with survival ≥ 5 years after BrM diagnosis.Materials/methods: We identified 1,370 patients diagnosed with BrM at a tertiary cancer center between 2008 and 2015 who either died or survived ≥ 5 years. Patients censored before 5 years were excluded from the analysis (N = 66). Multivariable logistic regression was used to characterize predictors of long-term (i.e., ≥ 5 years) survival after BrM diagnosis (odds ratios > 1 indicated a greater odds of long-term survival). Median survival for subgroups was calculated with the Kaplan-Meier method; comparisons were made with the log-rank test.Results: Among all 1,304 patients, median survival after BrM diagnosis was 10.8 months. In total, 123 patients (9.4%) survived ≥ 5 years. On multivariable logistic regression, significant predictors of survival ≥ 5 years included: breast as the primary tumor site vs. the reference of non-small cell lung cancer (NSCLC) (OR: 2.44 [95% CI, 1.23-4.83], P = 0.01), high Karnofsky performance score (KPS) (90-100) vs. low KPS (< 90) (OR: 2.32 [95% CI, 1.48-3.62], P < 0.001), and lack of progressive extracranial disease at time of BrM diagnosis (OR: 2.33 [95% CI, 1.47-3.70], P < 0.001). Factors significantly associated with not surviving ≥ 5 years included: receipt of whole brain radiation therapy vs. the reference of SRT as initial management (OR: 0.30 [95% CI, 0.13-0.70], P = 0.005), presence of 2-4 BrM vs. 1 BrM (OR: 0.63 [95% CI, 0.40-1.00], P = 0.05), an increasing number of extracranial sites of disease (OR: 0.73 per additional site [95% CI, 0.59-0.90], P = 0.003), and an increasing number of systemic therapy regimens for metastatic disease prior to diagnosis of BrM (OR: 0.64 per additional regimen [95% CI, 0.50-0.84], P = 0.001). When limiting to patients with NSCLC for whom EGFR and ALK status were known, there were significant differences in survival among patients with an ALK rearrangement, EGFR mutation, or neither (median survival of 30.9, 15.0, and 12.7 months, respectively, P = 0.04). Subsetting patients with breast cancer based on receptor subtype, there were significant differences in survival among patients with HER2-positive, hormone receptor-positive/HER2-negative, or triple-negative breast cancer (median survival of 26.0, 11.2, and 6.5 months, respectively, P < 0.001).Conclusion: Although patients with BrM generally have a poor prognosis, select patients live for ≥ 5 years. Multidisciplinary teams caring for favorable sub-populations should consider the long-term impact of oncologic therapy when formulating treatment recommendations.Author Disclosure: N. Lamba: None. D.N. Cagney: Research Grant; NhTheraguix, Viewray. P.J. Catalano: None. P. Wen: None. D. Haas-Kogan: Research Grant; Novartis; Cellworks. A.A. Aizer: Research Grant; Varian. Consultant; Novartis. Advisory Board; Seattle Genetics. [ABSTRACT FROM AUTHOR]

Treatment options for hydrocephalus include endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS). Methods A systematic literature search was conducted via PubMed, EMBASE and Cochrane Library through 11/29/2018 identifying studies evaluating failure and complication rates, following ETV or VPS. Conclusions No significant differences were observed in the failure rate when comparing ETV to VPS for the treatment of obstructive hydrocephalus. [Extracted from the article]

There is recurrence at some point following initial resection or radiosurgery in about 50% of patients previously treated for brain metastases (BMs); yet, little is known about the optimal management of recurrent BMs. To better understand the management of recurrent brain metastases, we carried out a systematic review and meta-analysis to describe outcomes of craniotomy for recurrent BMs after resection or stereotactic radiosurgery, with particular attention to recurrence in the previous resection cavity. Studies were grouped by initial local treatment strategy to compare resection after resection (RAR) vs. resection after stereotactic radiosurgery (RAS). [Extracted from the article]

Brain metastases from esophageal cancer are a rare and understudied form of metastatic spread with limited treatment options. We characterized the clinical and genomic features of esophageal cancer brain metastases. We identified 129 patients who were diagnosed with brain metastases secondary to esophageal cancer at a single institution between 2002 and 2020. Survival analysis was performed using multivariable Cox proportional hazards regression. Results of targeted next-generation sequencing (NGS) panels were obtained for 56 patients representing 62 adenocarcinoma samples and compared to a cohort of 1344 esophageal adenocarcinoma samples identified from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) v11.0. ERBB2 / HER2 amplified/overexpressed (HER2 +) status was determined using routine clinical assays and/or NGS results. Median age at the time of esophageal cancer diagnosis was 63 years (interquartile range 58-68 years). 14% of the cohort (n=18) was female, 93% (n=120) had adenocarcinoma, and 98% (n=126) of primary tumors involved the distal esophagus and/or gastroesophageal junction. 50% (n=64) of patients had distant metastases at presentation, including 18 patients with brain metastases. 51% (n=66) underwent resection for brain metastases, and 84% (n=108) underwent radiation therapy (n=26 for whole brain, n=55 for partial brain or stereotactic, and n=27 for both). With median follow-up of 19 months for the entire cohort, median overall survival following primary cancer diagnosis was 22 months and significantly higher for HER2 + disease (31 vs 19 months, hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87, P =0.004). For patients without brain metastases initially, the median time between initial diagnosis and brain metastasis diagnosis was 13 months and significantly higher for patients without distant metastasis initially (14 vs 12 months, HR 0.59, 95% CI 0.39-0.89, P =0.012). Median overall survival after brain metastasis diagnosis was 7 months and significantly higher for HER2 + disease (14 vs 4 months, HR 0.60, 95% CI 0.45-0.82, P =0.001). NGS results were notable for an enrichment of HER2 high amplification events (42% vs 19%, P <0.0001), HER2 mutations (10% vs 4%, P =0.036), and TP53 mutations (97% vs 73%, P <0.00001; all with Fisher's exact test) compared to the GENIE cohort. Esophageal cancer brain metastases are associated with a poor prognosis and have a distinct molecular profile. Further efforts are necessary to elucidate the drivers of this unique and aggressive entity in order to develop novel treatment strategies. [ABSTRACT FROM AUTHOR]