A Biological Basis for Local Failure After Lung Stereotactic Body Radiation Therapy

Volume 96  Number 2S  Supplement 2016

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Results: Maximum point dose prediction to the esophagus demonstrated a cross-validation accuracy of 87%, and the maximum dose to 5cc demonstrated a respective value of 79%. As calculated during the training phase of the algorithm, the largest optimized weighting factor was placed on GTV-to-esophagus distance (a factor of 10 greater than the second largest weighting factor), indicating a strong correlation between this anatomic feature and both dosimetric endpoints. GTV volume and ITV volume also achieved relatively high weighting factors, while other features seemed to be less-relevant in driving the optimization to a solution. Conclusion: This pilot study shows that it is feasible to predict dosevolume endpoints based on patient-specific anatomic features. The developed methodology can potentially help to identify patients whom are at risk for higher OAR doses, thus improving the efficiency of treatment planning. Author Disclosure: K. Lafata: Research Grant; NIH. J. Cai: Research Grant; NIH. L. Ren: Research Grant; NIH. Q. Wu: None. J.C. Hong: None. C.R. Kelsey: None. F. Yin: Research Grant; NIH.

CI 0.21-0.87). Neither ATT (HR 0.81, 95% CI 0.46-1.43) nor systemic therapy (HR 1.08, 95% CI 0.55-2.10) were associated with improved overall survival. Conclusion: NSCLC patients with brain-only metastases treated with intracranial SRS most commonly failed in the brain or thorax first. Long term survival is possible with 23% of patients living at least 3 years after diagnosis of brain metastases. Further investigation into the effects of WBRT, ATT and systemic therapy on outcomes in this patient population is necessary. Author Disclosure: D.P. Bergsma: Employee; University of Rochester Medical Center. M.J. Moravan: None. J.S. Suri: None. K.Y. Usuki: Employee; University of Rochester Medical Center. D.P. Singh: None. M.T. Milano: None.

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Purpose/Objective(s): Outcomes of stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (ES-NSCLC) show high rates of local control associated with 100 Gy biologic equivalent dose (BED). To mitigate effects of attrition due to intercurrent illness, we examined predictors of local failure (LF) in in a sub-set of patients with sufficient follow up to assure that if LF was to occur, it would be identified. Materials/Methods: From an IRB-approved lung SBRT registry (2003 to 2015), we selected patients treated curatively for ES-NSCLC clinical stage T1-T3, without chest wall invasion. We found 90% of LF occurred within 24 months of treatment. To minimize the effect of loss to follow up or death from inter-current illness, we defined a selected sub-set with either local failure or a minimum of 24 month radiographic follow-up. We limited this subset to patients with a tissue confirmation (at diagnosis or recurrence) of ES-NSCLC and no history of lung cancer in the 5 years prior to SBRT (n Z 175). Predictors of LF were determined using proportional hazards modeling and actuarial rates of local control were determined from Kaplan-Meier estimates. The results were then confirmed in the larger cohort of SBRT cases (n Z 740). Results: Cohorts were well balanced in age, performance status, tumor size, and prescription dose. There were significantly fewer comorbidities (median Charlson Co-morbidity Score 2 v. 3, P Z 0.009) and longer follow up (33.1 v. 15.5 months) in the selected sub-set (n Z 175). On univariate analysis, squamous cell (SC) histology (HR 3.06 95% CI 1.70-5.80 P Z 0.0002), larger tumor size (HR 1.35 95% CI 1.07-1.66 P Z 0.01) and lower BED (HR 1.012 95% CI 1.002-1.024 P Z 0.01) were predictive of higher rates of LF in the sub-set. On multivariable analysis, SC histology (HR 3.06, P Z 0.0002) and lower BED (HR 1.011, P Z 0.024) remained significantly associated with a higher risk of LF, whereas size was of borderline significance (HR 1.24, P Z 0.052). For patients treated to doses >100 Gy BED (n Z 170), higher dose (100 to 180 Gy BED) was associated with improved local control for SC tumors (P Z 0.009) but not for adenocarcinomas (AC) (P Z 0.74). In the overall cohort with a confirmed tissue diagnosis (n Z 451), patients with SC tumors had a significantly higher three-year rate of LF compared to patients with AC (27.9% v. 12.7%, P Z 0.03). Conclusion: We validated tumor size and BED as predictors of local failure after SBRT for ES-NSCLC. In addition, this is the first study to demonstrate differential dose responses by histology. A 100 Gy BED threshold is insufficient to maximize local control in squamous tumors. Histology should be considered as a stratification variable for lung SBRT trials and further studies are warranted to characterize the response of lung lineages to hypofractionated radiation treatment. Author Disclosure: N.M. Woody: None. K.L. Stephans: None. M. Andrews: None. T. Zhuang: None. C.A. Reddy: None. P. Xia: Research

Patterns of Systemic Failure in Non-Small Cell Lung Cancer (NSCLC) Patients With Brain-Only Metastases Treated With Intracranial Stereotactic Radiosurgery (SRS) D.P. Bergsma, M.J. Moravan, J.S. Suri, K.Y. Usuki, D.P. Singh, and M.T. Milano; Wilmot Cancer Institute, University of Rochester, Rochester, NY Purpose/Objective(s): We sought to determine the long term outcomes, including patterns of systemic recurrence, in NSCLC patients with brainonly metastases treated with intracranial SRS. Materials/Methods: We retrospectively identified 370 patients with NSCLC treated with intracranial SRS at our institution from 2001-2015. From staging body (73% PET-CT) and brain (97% MRI) scans, 142 were found to have metastases limited to the brain. All radiography and clinic records were reviewed to determine the timing and location of recurrences; 117 had both body and brain post-SRS imaging available for review. Cox proportional hazards model was used to measure the effect of treatment variables on outcome. Results: The median age at SRS was 63 (range 41-88) years and median DS-GPA was 2.5 (range 1.0-4.0). Patients were 54% male and 46% female. Brain metastases were most commonly adenocarcinoma (80%), synchronous (67%) and solitary (62%). Median cumulative brain metastasis volume at diagnosis was 4.58 (range 0.03-79.8) cc. ALK/ EGFR receptor status was available in 36 patients (78% negative, 17% EGFR+ and 5% ALK+). WBRT was given to 72 patients (62%), either upfront (67%), as salvage (29%) or both (4%). The median interval from diagnosis of brain metastases to SRS was 49 (range 8-593) days and median SRS isocenter dose was 16.5 (range 9-25) Gy; the 80% isodose line covered 99% of the target (GTV Z PTV). Among patients with synchronous metastases, 38 (51%) received aggressive thoracic therapy (ATT), i.e. surgery, SBRT or chemoradiation, and 57 (76%) received systemic therapy prior to extra-cranial progression. Median follow up was 16.5 (range 1.9-136.8) months. Of those who recurred (n Z 100), site of first failure was outside the brain in 42%, within the brain in 49% and both in 9%. Location of first (cumulative) recurrences were 26% (38%) local CNS, 42% (58%) distant CNS, 20% (27%) primary lung tumor, 20% (33%) regional lymph nodes (LNs), 22% (42%) distant lung, 4% (17%) non-regional LNs, 11% (27%) bone, 10% (21%) liver, 5% (19%) adrenal gland and 7% (20%) other site(s). Median overall and progression free survival were 17.0 (range 2.1-136.8, upper quartile 31.0) months and 8.5 (range 1.4-136.8, upper quartile 17.2) months respectively. Causes of death (n Z 89) were intracranial (38%) or extra-cranial (45%) malignancy or other (17%), with 28 (24%) patients still alive at the time of analysis. Patients receiving ATT (but not systemic therapy alone) had decreased risk of extra-cranial first recurrence (HR 0.43, 95%

3038 A Biological Basis for Local Failure After Lung Stereotactic Body Radiation Therapy N.M. Woody, K.L. Stephans, M. Andrews, T. Zhuang, C.A. Reddy, P. Xia, G.M. Videtic, and M. Abazeed; Cleveland Clinic, Cleveland, OH

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International Journal of Radiation Oncology  Biology  Physics

Grant; Siemens Medical Solutions, Philips Medical Systems. G.M. Videtic: None. M. Abazeed: None.

Purpose/Objective(s): Stereotactic body radiation therapy (SBRT) is commonly considered the main treatment option for patients with stage I non-small cell lung cancer (NSCLC). Many studies have reported that the maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) of the primary tumor has prognostic value for resected NSCLC. The purpose of this study was to determine whether SUVmax is a predictor of disease-free survival (DFS) in patients with stage I NSCLC after SBRT. Materials/Methods: In all patients, the diagnosis was pathologically or cytologically confirmed. The patients held their breath using a respiratory monitoring system. The patients were scanned 3 times to obtain CT data sets. The 3 data sets were fused together, and the gross tumor volume (GTV) was contoured to each data set. The GTV was totaled to calculate internal target volume (ITV). Planning target volume (PTV) was determined by adding a 5-mm margin around the ITV. The leaf margin was 3 mm. In principle, the prescription dose of 48 Gy was delivered in 4 fractions at the isocenter using 6 MV photon beams. FDG-PET was performed at our institution before SBRT. The median time from FDG-PET/CT to SBRT was 6 weeks (range, 2-12 weeks).

3039 The Features and Prognostic Impact of Extracranial Metastases in Patients With EGFR Mutant Lung Adenocarcinoma J. Bi,1 G. Han,1 X. Wei,1 X. Ying,1 X. Zhou,1 D. Hu,1 and W. Zhen2; 1 Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, China, 2University of Nebraska Medical Center, Omaha, NE Purpose/Objective(s): Epidermal growth factor receptor (EGFR) mutations have been demonstrated to be both predictive and prognostic for patients with lung adenocarcinoma. In our previous study, we have demonstrated that brain metastases were more common among patients with EGFR mutant lung adenocarcinoma. However, the association of EGFR mutation and extracranial metastases (ECM) as well as its prognostic implications remain inconclusive. The purpose of this study was to explore the potential association between EGFR-mutation and the risk of ECM in patients with lung adenocarcinoma. Materials/Methods: 234 patients between March 2007 and December 2014 were included in this retrospective study. All patients were tested for EGFR mutational status. The relationships between EGFR mutation and ECM at the initial presentation and at the last follow-up were analyzed. In the subgroups analyses, the relationships between EGFR-mutation and metastases in different organs including bone, pleural effusion, intra-pulmonary, liver, adrenal gland and the other organs were also analyzed. Results: 108 out of 234 (46.2%) patients had EGFR mutations amongst 141 patients (60.3%) had developed ECM during their disease course and 87 patients (37.2%) were found to have ECM at the initial diagnosis. The frequency of EGFR mutation was not different in patients with ECM at the initial diagnosis (48.3% vs. 51.7% [Wild-type], P Z 0.616) or at the end of our follow-up (50.4% vs. 49.6% [Wild-type], P Z 0.112). Further analysis indicated that the EGFR mutational status could not predict the overall risk of ECM. In subgroup analyses, there were also no association between the EGFR-mutation and the metastases in different organs, except for bone. 79 patients (33.8%) had developed bone metastases (BM) during the disease course amongst 47 (20.1%) had BM at their initial diagnosis. The frequency of EGFR mutation was statistically higher for patients with BM at the initial diagnosis (25.9% vs. 15.1%, P Z 0.039) and at the last followup (41.7% vs. 27%, P Z 0.018). A strong association between EGFR mutational status and BM was observed (OR Z 2.084, 95% CI Z 1.0494.142, P Z 0.036) at the initial diagnosis by multivariate logistic regression analysis. Among those 187 patients without BM at initial diagnosis, 1- and 2-year accumulative rates of subsequent BM were significantly different between the patients with EGFR-mutant and EGFR-wild disease (20.4% vs. 9.2%, 28.8% vs. 17.5%; P Z 0.026). Additionally, the patients with BM had a worse median survival (23.84.1 vs. 61.318.6 months, P Z 0.000). Conclusion: In our study, only BM in patients with ECM was found to be significantly correlated with EGFR mutation status during their disease course. Patients with EGFR-mutant disease had a higher incidence of BM, which may represent one of the distinct clinical features for EGFR-mutant tumors. Bone metastasis was also found to be a negative predictor for survival. Further molecular studies should be conducted to investigate the potential mechanisms. Author Disclosure: J. Bi: None. G. Han: None. X. Wei: None. X. Ying: None. X. Zhou: None. D. Hu: None. W. Zhen: None.

3040 Pretreatment Maximum Standardized Uptake Value on 18FFluorodeoxyglucose Positron Emission Tomography Is a Predictor of Outcome for Stage I Non-Small Cell Lung Cancer After Stereotactic Body Radiation Therapy H. Tanaka, T. Yamaguchi, M. Kawaguchi, S. Okada, and M. Matsuo; Gifu University, Gifu, Japan

Abstract 3000; Table 1. Summary of univariate analysis of DFS. Parameters Age Gender Histology OTT Diameter BED SUVmax

Hazard Ratio (95% CI) p value 0.965 Male vs. Female 1.007 Adenocarcinoma vs. the Others 0.566 0.981  30 vs. < 30 mm 2.695 1.068  8 vs. < 8 3.739

(0.904-1.030) (0.275-3.688) (0.186-1.721) (0.795-1.211) (0.901-8.058) (0.921-1.237) (1.236-11.311)

0.2856 0. 9910 0.3159 0.8615 0.0761 0.3841 0.0195

Results: Forty-two patients were enrolled in this study. The median follow-up period was 21 months (range, 3-104 months). Regional lymph node metastasis and distant metastasis were observed in 7 (16.7%) and 4 (9.5%), respectively. The median SUVmax was 5.7 (range, 2.2-22.0). The 2-year DFS was 86% for the low SUVmax group (< 8.0) and 48% for the high SUVmax group ( 8.0). In univariate analysis, SUVmax (< 8 vs.  8) was significantly correlated with DFS. Multivariate analysis included variables with p values < 0.10 and showed that only SUVmax was significantly correlated with DFS. Conclusion: Pretreatment SUVmax on FDG-PET predicted the DFS in patients with stage I NSCLC after SBRT. Author Disclosure: H. Tanaka: None. T. Yamaguchi: None. M. Kawaguchi: None. S. Okada: None. M. Matsuo: None.

3041 Patterns of Failure After Hypofractionated Intensity Modulated Radiation Therapy for Patients With Non-Small Cell Lung Cancer Y. Qian,1 E. Pollom,1 B.Y. Durkee,2 R. von Eyben,3 M.F. Gensheimer,4 D.B. Shultz,5 M. Diehn,4 and B.W. Loo, Jr4; 1Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, 2Stanford Cancer Institute, Stanford, CA, 3Stanford University, Stanford, CA, 4Stanford University School of Medicine, Stanford, CA, 5Princess Margaret Cancer Centre, Toronto, ON, Canada Purpose/Objective(s): Alternative treatment regimens are needed for patients with non-small cell lung cancer (NSCLC) who cannot receive definitive treatment with concurrent chemoradiation, surgery, or stereotactic ablative radiation therapy (SABR). A Phase 1 dose escalation trial of hypofractionated radiation therapy (RT) for poor-performing