Schild, Steven E.

9522 Background: Many MSCC patients live long enough to develop a recurrence in the irradiated spinal area. This is the first prospective study comparing different RT schedules for local control (LC) of MSCC. Methods: 265 patients treated with RT alone (1/06–12/07) were included in this prospective non-randomized study. The primary goal was to compare short-course (1×8 Gy/5×4 Gy, N=131) and long-course RT (10×3 Gy/15×2.5 Gy/20×2 Gy, N=134) for 1-year LC. Secondary endpoints were motor function and 1-year survival (OS). Dutch patients received short-course, and German patients long-course RT. The analysis of LC (no MSCC recurrence in the irradiated spinal area) included the 224 patients with improvement or no change of motor deficits during RT. The difference in 1-year LC was previously reported to be 14% between short- and long-course RT. For a statistical power of 90 % (significance level 5%), ≥218 patients were required to detect this difference. Univariate analyses (UVA) for LC and OS were performed with Kaplan-Meier-method and log-rank test, multivariate analyses (MVA) with the Cox proportional hazards model. UVA and MVA for motor function were performed with the ordered-logit-model. Eleven additional factors were evaluated. Results: 1-year LC was 61% after short-course RT and 81% after long-course RT (P=0.005). On MVA, improved LC was only associated with long-course RT (P=0.018). Motor function improved in 37% after short- and 39% after long-course RT (P=0.95). Improved motor function was associated with better performance status (P=0.015), favorable tumor (P=0.034), and slower development of motor deficits (P<0.001). 1-year OS was 23% after short- and 30% after long-course RT (P=0.28). On MVA, improved OS was associated with better performance status (P<0.001), no visceral metastases (P<0.001), involvement of 1–3 vertebrae (P=0.040), ambulatory status (P=0.038), and bisphosphonates (P<0.001). Conclusions: Long-course RT was associated with better LC, similar functional outcome, and similar OS compared to short-course RT. Patients with a favorable OS prognosis should receive long-course RT, and those with a poor OS prognosis should receive short-course RT. [Table: see text]

8085 Background: Historically, tumor response has been the primary endpoint in phase II (P2) trials in ED-SCLC. We investigated the suitability of alternate PFS based endpoints to predict OS as early evidence of efficacy in the P2 setting. Methods: Individual patient (pt) data from 942 pts from 11 previously untreated ED-SCLC P2 and phase III (P3) platinum- or paclitaxel-based treatment trials were pooled. Best response (BR), response confirmed (RC), objective status at 16 weeks (RR16), and PFS rate at 5 and 6 months were considered. Percent agreement (PA) and kappa (k) for PFS5, PFS6, BR, RC, and RR16 with OS at 12 months (OS12) was calculated on a per-pt basis and predictive utility was assessed using the area under the receiver operating characteristic (A- ROC) curve in logistic models. Cox models were used to assess the prognostic impact of the endpoints on subsequent survival, using landmark analysis. Results: The median OS and PFS were 9.6 m and 5.5 m, respectively. PFS5 and PFS6 had the highest PA, k, and A-ROC values, and were predictive of subsequent survival in the landmark analysis (p <0.0001; c-statistics ≥ 0.60). While RR16 and BR were significantly associated with subsequent survival (p<0.0001, c-statistics of 0.61 and 0.57, respectively) the PA, k, and A-ROC values were lower. Conclusions: PFS rate at 5 and 6 months is more predictive of 12-month OS and subsequent survival than tumor response in untreated ED-SCLC. PFS based endpoints should be routinely used as primary endpoints in P2 trials within ED-SCLC. [Table: see text] No significant financial relationships to disclose.

7544 Background: NCCTG N0028 was a trial that determined the MTD of RT that could be given with carboplatin & paclitaxel was 74 Gy/34 fractions. This secondary analysis was performed to determine the survival of pts treated on this trial. Methods: Eligible pts had medically or surgically unresectable NSCLC, PS=0–1, weight loss <10% in the prior 3 months(mo), no prior therapy, adequate laboratory & pulmonary functions. Included were 25 pts with clinical stages I (4pts), II (1 pt), IIIa (12 pts), & IIIb (8 pts). Treatment included: weekly I.V. paclitaxel (50mg/m2) & carboplatin (AUC=2) during RT. The RT included 2 Gy daily to an initial dose of 70 Gy. The total dose was increased in 4 Gy increments until the MTD was determined. RT was delivered with 3-D treatment planning but no elective nodal RT. Three pts received 70 Gy, 18 pts received 74 Gy, & 4 pts received 78Gy. Results: Pts were followed until death or from 10–67 mo (median: 28mo) in those alive at last evaluation. The median survival (MS) of the entire cohort was 42mo. The 5 stages I-II pts had a MS of 53 mo & the 20 stage III pts had MS of 42mo. Conclusions: Standard dose RT is unable to sterilize disease in the majority of pts with unresectable NSCLC. While the addition of chemotherapy has significantly improved survival of these pts, the MS is generally 15–24 mo. These preliminary results suggest higher than standard doses of RT may improve disease control & prolong survival. A phase III trial comparing standard-dose RT(60Gy) to high-dose RT (74Gy) is open and should more definitively address the issue of RT dose with concurrent chemotherapy for unresectable NSCLC. Future technological improvements in imaging & targeting will provide methods to safely administer even greater RT doses which will likely further improve disease control. No significant financial relationships to disclose.

7506 Background: The incidence of central nervous system (CNS) metastases is high in patients with locally advanced non-small cell lung cancer. Brain as an only site of relapse appears increasingly common as loco-regional and extra-cranial systemic treatment improves. There is not standard agreement as to how to address this risk. Methods: Patients with stage III NSCLC without progression of disease after loco-regional treatment with surgery and/or radiation therapy with or without chemotherapy were eligible. Participants were randomized to prophylactic cranial irradiation (PCI) or observation and stratified by stage (IIIA or B), histology (non-squamous or squamous) and therapy (surgery or no surgery). PCI was delivered once daily at 2Gy per fraction to 30Gy. The primary endpoint of the study was overall survival (OS). Secondary endpoints were disease free survival (DFS) and the impact of PCI on incidence of CNS metastases, neuropsychological function, and quality of life (QoL). Kaplan- Meier estimation with the log-rank test was used for OS and DFS and the logistic regression model was used for calculating the incidence of CNS metastasis. Results: Total accrual was 356 patients of the targeted 1058 between 9/19/02 and 8/30/07. The study was closed early due to slow accrual. 340 patients were evaluable. One year OS (p=0.86, 75.6 % and 76.9% for PCI and observation) and one year DFS (p=0.11, 56.4% and 51.2% for PCI and observation) were not statistically significantly different. However, CNS metastatic rate at 1 year was statistically significantly different with CNS relapse 7.7% vs. 18% for PCI vs. observation (p=0.004). Logistic regression showed that the patients in the observation arm are 2.52 times more likely to develop CNS metastases than those in the PCI arm (odds ratio=2.52, 95% CI=(1.32–4.80)). Conclusions: PCI in patients without progressive disease after loco-regional therapy for III NSCLC significantly decreases the rate of CNS metastases. This study did not show a statistically significant difference in OS or DFS. Forthcoming analysis of the impact of PCI on neuropsychological function and QoL will influence the recommendations regarding the standard use of PCI. No significant financial relationships to disclose.

2075 Background: This study was performed to create and validate scoring systems to estimate survival and intracerebral local control at 6 months of patients irradiated for brain metastases. Methods: Data of 1,797 patients irradiated for brain metastases (1,346 whole-brain radiotherapy [WBRT], 131 radiosurgery [RS], 61 WBRT + RS, 259 resection + WBRT) were retrospectively analyzed. Patients were randomly assigned to the test group (N = 1,198) or the validation group (N = 599). In the test group, multivariate analyses (MVA, Cox proportional hazards model) were performed for survival (OS) and local control (LC). Based on the MVA results, two scoring systems were developed, one for OS and another for LC. The scores included the prognostic factors found significant on MVA. Age, performance status, extracranial metastases, interval from tumor diagnosis to RT, and number of brain metastases were significant for OS. Tumor type, performance status, interval from tumor diagnosis to RT, and number of brain metastases were significant for LC. The score for each factor was determined by dividing the 6-month OS or LC rate (%) by 10. The total score represented the sum of the scores for each factor. For OS, total scores ranged from 15–30 points, and patients were divided into three groups (15–19, 20–25, and 26–30 points). For LC, total scores ranged from 14–27 points, and patients were divided into three groups (14–18, 19–23, and 24–27 points). Results: In the test group, the 6-month OS rates were 9 ± 1% for patients with scores of 15–19 points, 41 ± 2% for those with 20–25 points, and 78 ± 2% for those with 26–30 points (p < 0.0001). The corresponding OS rates in the validation group were 7 ± 2%, 39 ± 3%, and 79 ± 3%, respectively (p < 0.0001).In the test group, the 6-month LC rates were 17 ± 3% for patients with 14–18 points, 49 ± 3% for those with 19–23 points, and 77 ± 2% for those with 24–27 points (p < 0.0001). The corresponding LC rates in the validation group were 19 ± 4%, 52 ± 4%, and 77 ± 3%, respectively (p < 0.0001). Conclusions: Patients irradiated for brain metastases can be grouped with these scores to estimate OS and LC. The OS and LC rates of the validation group were almost identical to the test group, which demonstrates the high validity and reproducibility of both scores. No significant financial relationships to disclose.

e21575 Background: The clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine (NE) tumors is unknown; we therefore conducted a population based analysis to evaluate the implications of brain metastases in these patients. Methods: The NCDB database was queried to identify patients with stage IV bronchopulmonary NE tumors treated between the years of 2004-2012. Patients were split into two groups based on the presence of brain metastases at diagnosis and survival probabilities with multivariate models were performed. Results: A total of 7,725 patients with Stage IV bronchopulmonary NE tumors were identified. The histological subtypes studied in this cohort were NE carcinoma (65.4%), large cell NE carcinoma (30.5%), typical carcinoid (2.8%) and atypical carcinoid (1.3%) . The patients included in this study were mainly white (86.4%) men (56.8%) with a median age of 67 years who had liver (9.5%), bone (6.2%) and brain (5.9%) metastases at diagnosis. The median overall survival (OS) of the cohort was 5.59 (95% CI: 5.4-5.8) months, but when OS was stratified by histological subtype it was significantly better in patients with typical carcinoid (table). In the whole cohort, the median OS did not differ between patients with and without brain metastases (5.55 vs. 5.68; p = 0.24). However, a sensitivity analysis by histology showed that the presence of brain metastases worsen the median OS of patients with typical carcinoid only (15.1 vs 4.6, p = 0.04). An adjusted multivariate analysis restricted to patients with brain metastases showed that administration of systemic chemotherapy (HR:0.5; 95% CI:0.35-0.72, p < 0.001) and resection of distant metastases (HR:0.5; 95% CI:0.29-0.88, p = 0.017) were the two most powerful independent prognostic factors. Conclusions: The presence of brain metastases negatively impact survival of patients with typical carcinoids but not in those with the other histological subtypes included in this study. Staging MRI should be strongly considered at diagnosis in patients with bronchopulmonary NE tumors, due to the sizable proportion of these patients presenting with brain metastases and also due to its prognostic value in a subset of this population. [Table: see text]

An easy-to-use survival score was developed specifically for older patients with cerebral metastases from colorectal cancer, and was compared to existing tools regarding the accuracy of identifying patients who die in ≤6 months and those who survive for ≥6 months. The new score was built from 57 patients receiving whole-brain irradiation. It included three groups identified from 6-month survival rates based on two independent predictors (performance status and absence/presence of non-cerebral metastases), with 6-month survival rates of 0% (0 points), 26% (1 point), and 75% (2 points), respectively. This score was compared to diagnosis-specific scores, namely the diagnosis-specific graded prognostic assessment (DS-GPA), the Dziggel-Score and the WBRT-30-CRC (whole-brain radiotherapy with 30 Gy in 10 fractions for cerebral metastases from colorectal cancer) score and to a non-diagnosis-specific score for older persons (Evers-Score). Positive predictive values were 100% (new score), 87% (DS-GPA), 86% (Dziggel-Score), 91% (WBRT-30-CRC), and 100% (Evers-Score), respectively, for patients dying ≤6 months, and 75%, 33%, 75%, 60%, and 45%, respectively, for survivors ≥6 months. Of the five tools, the new score and the Evers-Score were most precise in identifying patients dying ≤6 months. The new score and the Dziggel-Scores were best at identifying patients surviving ≥6 months. When combining the results, the new score appeared preferable to the existing tools. The score appears not necessary for patients with additional liver metastases, since their 6-month survival rate was 0%.

Objectives: To report long-term outcomes of nonmelanoma skin cancer (NMSC) in immunosuppressed cardiac and liver transplant recipients (CLTR). Materials and Methods: The authors reviewed CLTR at the Mayo Clinic in Arizona from 1986 to 2013. Patient and tumor characteristics were recorded. Survival rates were calculated using the Kaplan-Meier method. Patient-specific and lesion-specific analyses were performed. Univariate and multivariate cox regressions were performed for comparisons. Results: Seven-hundred and forty-seven patients underwent cardiac (138) or liver (609) transplantation and of these, 97 patients (13%) developed 382 invasive NMSC. The median follow-up was 11 (range, 3 to 27) years for surviving patients. Primary treatment was mainly surgery alone. At 10 years, the local recurrence (LR) rate was 20% (95% confidence interval, 15%-28%), and 14% of patients had multiple LRs. At 10 years, LR rates were higher for T3/T4 tumors when compared with T1/T2 tumors (32.5% vs. 20%, P=0.05). At 10 years, overall survival was 79% (95% confidence interval, 64%-88%). On multivariate analysis, age 61 years and more demonstrated inferior overall survival (P<0.01). Conclusions: This is the first study describing the AJCC 8th edition stage-based patterns of recurrence and long-term outcomes of surgically managed NMSC in a large cohort of immunosuppressed CLTRs. T3 and T4 tumors recur more often than early stage tumors. Further study is required to identify factors related to recurrence and guide upfront treatment intensification in this high-risk population.

Abstract The incidence of brain metastasis is increasing as improvements in systemic therapy lead to increased survival. This provides new and challenging clinical decisions for patients who are trying to balance the risk of recurrence or progression with treatment-related side effects, and it requires appropriate management strategies from multidisciplinary teams. Improvements in prognostic assessment and systemic therapy with increasing activity in the brain allow for individualized care to better guide the use of local therapies and/or systemic therapy. Here, we review the current landscape of brain-directed therapy for the treatment of brain metastasis in the context of recent improved systemic treatment options. We also discuss emerging treatment strategies including targeted therapies for patients with actionable mutations, immunotherapy, modern whole-brain radiation therapy, radiosurgery, surgery, and clinical trials.