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Purpose: To review 10 years of using single-fraction lung stereotactic body radiation therapy (SF-SBRT) for medically inoperable peripheral early-stage lung cancer., Methods and Materials: An institutional review board-approved prospective lung SBRT data registry was surveyed until the end of December 2019 for all patients receiving SF-SBRT with minimum 6-month follow-up. Doses used were either 34 Gy or 30 Gy. Outcomes of interest included rates of local failure and overall survival (OS), as well as treatment-related toxicity graded per Common Terminology Criteria for Adverse Events version 3.0., Results: A total of 229 patients met the study criteria. Patient characteristics included female sex (55%); median age, 74.6 years (range, 47-94); and median Karnofsky Performance Status 80 (range, 50-100). Tumor characteristics included median diameter, 1.6 cm (range, 0.7-4.1); median positron emission tomography standardized uptake value maximum 6.1 (range, 0.8-24.3); and 63.6% of patients biopsied. SF-SBRT dose was 34 Gy in 72.1% cases and 30 Gy in 27.9%, with patient and tumor characteristics balanced between cohorts. Overall median follow-up times for 30 Gy and 34 Gy were 36.7 and 17.2 months, respectively (P < .0001). At analysis, 55.9% patients were alive. Two (0.9%) patients developed grade 3 toxicities, and none had grade 4/5 toxicities. Grades 1 to 2 pneumonitis and chest wall toxicity were seen in 7% and 12.7% patients, respectively. Median overall survival was 44.1 months. Rates of 2-year local, nodal, and distant failure were 7.3%, 9.4%, and 12.2%, respectively. There were no significant differences in outcomes by dose., Conclusions: This is the largest institutional series to date reporting on SF-SBRT outcomes for medically inoperable peripheral early-stage lung cancer and the first to report on a decade's experience in implementing this schedule. Outcomes from this analysis are comparable to published results from 2 randomized trials and validate the use of this schedule in routine practice. In the absence of phase 3 trials, this study should encourage increased use of SF-SBRT for inoperable tumors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Clinical validation of protocol-specified dosimetric constraints for the proximal bronchial tree (PBT) is limited for central non-small cell lung cancer treated with stereotactic body radiation therapy. We sought to validate Radiation Therapy Oncology Group (RTOG) PBT constraints with a large institutional data set., Methods and Materials: Lesions ≤2 cm from the PBT treated with definitive stereotactic body radiation therapy from 2009 to 2016 were identified from a prospective registry of 1462 patients. Every PBT dose and volume combination, ranging from 0 cGy to 8000 cGy in increments of 10 cGy and volumes ranging from 0.03 cm 3 to 50 cm 3 in increments of 0.03 cm 3 , was analyzed. The sensitivity and specificity of these endpoints for identifying pulmonary toxicity were calculated. Pulmonary toxicity was classified as pneumonitis or nonpneumonitis toxicity (NPT) (fistula, stenosis, necrosis, hemoptysis, clinically significant pleural effusion). The optimal dosimetric predictor was chosen by calculation of F-score (highest sensitivity and specificity)., Results: The study included 132 patients, with 26.0-month median follow-up. Eight grade ≥2 NPT (2 grade 5) and 8 grade 2 pneumonitis toxicities were observed. The PBT dosimetric endpoint with the highest F-score for identification of grade 2 to 5 NPT was D0.03cc ≤5000 cGy and that for grade 3 to 5 NPT was D0.33cc ≤4710 cGy, with sensitivity and specificity of 87.5% and 76.6% and 100.0% and 85.7%, respectively. Applying the RTOG 0813 PBT constraints to our data set achieved a sensitivity and specificity of 33.3% and 92.1% for D4cc ≤1800 cGy and 37.5% and 92.7% for D0.03cc ≤5250 cGy for identification of grade 2 to 5 NPT. A PBT dosimetric correlation for pneumonitis toxicity could not be identified., Conclusions: This novel dosimetric analysis validates current RTOG constraints and emphasizes high-dose, small-volume constraints as better predictors for NPT. We demonstrated that a slightly lower maximum point dose PBT constraint may be optimal for identification of NPT. Validation of these findings in a larger cohort of patients with longer follow-up is necessary., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To examine the impact of stereotactic body radiation therapy (SBRT) dose on outcomes in early-stage non-small cell lung cancer in a large single-institution series., Methods and Materials: We reviewed 600 patients treated from 2003 to 2012 for early-stage non-small cell lung cancer. The SBRT dose was at physician discretion on the basis of tumor size and location. Peripheral tumors were treated to 60 Gy in 3 fractions (homogeneous planning), 48-50 Gy in 4-5 fractions, or 30-34 Gy in 1 fraction. Central tumors were treated to 50 Gy in 5 fractions, 60 Gy in 8 fractions, or 50 Gy in 10 fractions. Patient, tumor, and treatment factors were assessed for their impact on patterns of failure, toxicity, and survival., Results: An SBRT dose of 54-60 Gy in 3 fractions was associated with a statistically significant lower rate of local failure (LF) (4.3% at 2 years) compared with 30-34 Gy in 1 fraction (21%), 48-50 Gy in 4-5 fractions (15.5%), and 50-60 Gy in 8-10 fractions (13.3%). Lower pre-SBRT hemoglobin and higher positron emission tomography standardized uptake value were also associated with LF. Nodal failure, distant failure, and overall survival were similar between fractionation groups. Pulmonary toxicity (crude rate, any grade) was slightly higher for 3 fractions (5.0%) compared with 1 (3.2%) or 4-5 fractions (3.8%). Chest wall toxicity was also higher for 3 (23.7%) compared with 1 (8.6%) or 4-5 (7.7%) fraction regimens., Conclusions: Although higher biologically equivalent dose SBRT (150-180 Gy 10 ) may be associated with slightly lower LF, it was also associated with mildly increased toxicity and no difference in other patterns of failure or overall survival., (Copyright © 2017. Published by Elsevier Inc.)

Purpose: To determine the patterns of adjuvant chemoradiotherapy use in elderly patients treated with definitive surgical resection for squamous cell carcinoma of the head and neck with extracapsular extension (ECE) or positive margins and determine whether an association with overall survival (OS) exists with adjuvant concurrent chemoradiotherapy (CRT)., Methods and Materials: The National Cancer Database was queried to identify patients with SCC of the oral cavity, oropharynx, larynx, and hypopharynx who were treated with primary definitive surgery and adjuvant radiation therapy between 2004 and 2012. For elderly patients (aged >70 years) with pathology revealing ECE or positive margin, the benefit of concurrent chemotherapy was explored using multivariable Cox proportional hazards modeling., Results: A total of 7349 patients were identified meeting study criteria, of whom 1187 were elderly (aged >70 years) with a median follow-up of 30.6 months. Of these elderly patients, 445 had ECE or positive margin and represent the study population, of whom 187 (42%) received CRT. Delivery of CRT in this cohort increased over the study period, and intensity modulated radiation therapy was associated with increased use of CRT (odds ratio 2.07; P=.004). Increasing age was associated with reduced use of CRT (odds ratio 0.88; P<.001). Chemoradiotherapy was associated with a significant improvement in OS on multivariable analysis (hazard ratio 0.74; P=.04) and a trend toward significance on inverse propensity score analysis (hazard ratio 0.78; P=.051). Three-year OS was 53.8% in the CRT group, compared with 44.6% in the adjuvant radiation therapy-alone patients., Conclusions: The use of adjuvant CRT is increasing among elderly patients with resected squamous cell carcinoma of the head and neck exhibiting ECE or positive margins. Chemoradiotherapy was associated with an improvement in OS on multivariable analysis but not propensity-weighted analysis. Among fit elderly patients with ECE or positive margins after definitive surgical resection, concurrent chemotherapy can be carefully considered., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: A prognostic model for 5-year overall survival (OS), consisting of recursive partitioning analysis (RPA) and a nomogram, was developed for patients with early-stage non-small cell lung cancer (ES-NSCLC) treated with stereotactic ablative radiation therapy (SABR)., Methods and Materials: A primary dataset of 703 ES-NSCLC SABR patients was randomly divided into a training (67%) and an internal validation (33%) dataset. In the former group, 21 unique parameters consisting of patient, treatment, and tumor factors were entered into an RPA model to predict OS. Univariate and multivariate models were constructed for RPA-selected factors to evaluate their relationship with OS. A nomogram for OS was constructed based on factors significant in multivariate modeling and validated with calibration plots. Both the RPA and the nomogram were externally validated in independent surgical (n = 193) and SABR (n = 543) datasets., Results: RPA identified 2 distinct risk classes based on tumor diameter, age, World Health Organization performance status (PS) and Charlson comorbidity index. This RPA had moderate discrimination in SABR datasets (c-index range: 0.52-0.60) but was of limited value in the surgical validation cohort. The nomogram predicting OS included smoking history in addition to RPA-identified factors. In contrast to RPA, validation of the nomogram performed well in internal validation (r(2) = 0.97) and external SABR (r(2) = 0.79) and surgical cohorts (r(2) = 0.91)., Conclusions: The Amsterdam prognostic model is the first externally validated prognostication tool for OS in ES-NSCLC treated with SABR available to individualize patient decision making. The nomogram retained strong performance across surgical and SABR external validation datasets. RPA performance was poor in surgical patients, suggesting that 2 different distinct patient populations are being treated with these 2 effective modalities., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to determine outcomes of patients with node-negative medically inoperable non-small cell lung cancer (NSCLC) whose primary tumors exceeded 5 cm and were treated with stereotactic body radiation therapy (SBRT)., Methods and Materials: We surveyed our institutional prospective lung SBRT registry to identify treated patients with tumors >5 cm. Treatment outcomes for local control (LC), locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were assessed by Kaplan-Meier estimates. Toxicities were graded according to Common Terminology Criteria for Adverse Events version 4. Mean pretreatment pulmonary function test values were compared to mean posttreatment values., Results: From December 2003 to July 2014, 40 patients met study criteria. Median follow-up was 10.8 months (range: 0.4-70.3 months). Median age was 76 years (range: 56-90 years), median body mass index was 24.3 (range: 17.7-37.2), median Karnofsky performance score was 80 (range: 60-90), and median Charlson comorbidity index score was 2 (range: 0-5). Median forced expiratory volume in 1 second (FEV1) was 1.41 L (range: 0.47-3.67 L), and median diffusion capacity (DLCO) was 47% of predicted (range: 29%-80%). All patients were staged by fluorodeoxyglucose-positron emission tomography/computed tomography staging, and 47.5% underwent mediastinal staging by endobronchial ultrasonography. Median tumor size was 5.6 cm (range: 5.1-10 cm), median SBRT dose was 50 Gy (range: 30-60 Gy) in 5 fractions (range: 3-10 fractions). Eighteen-month LC, LRC, DFS, and OS rates were 91.2%, 64.4%, 34.6%, and 59.7%, respectively. Distant failure was the predominant pattern of failure (32.5%). Three patients (7.5%) experienced grade 3 or higher toxicity. Mean posttreatment FEV1 was not significantly reduced (P=.51), but a statistically significant absolute 6.5% (P=.03) reduction in DLCO was observed., Conclusions: Lung SBRT for medically inoperable node-negative NSCLC with primary tumors larger than 5 cm is safe and provides excellent local control with limited toxicity. The predominant pattern of failure in this population was distant failure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To review outcomes of 2 single-fraction lung stereotactic body radiation therapy (SBRT) schedules used for medically inoperable early stage lung cancer., Methods and Materials: Patients in our institution have been treated on and off protocols using single-fraction SBRT (30 Gy and 34 Gy, respectively). All patients had node-negative lung cancer measuring ≤5 cm and lying ≥2 cm beyond the trachea-bronchial tree and were treated on a Novalis/BrainLAB system with the ExactTrac positioning system for daily image guidance., Results: For the interval from 2009 to 2012, 80 patients with 82 lesions were treated with single-fraction lung SBRT. Fifty-five patients (69%) and 25 patients (31%) received 30 Gy and 34 Gy, respectively. In a comparison of 30 Gy and 34 Gy cohorts, patient and tumor characteristics were balanced and median follow-up in months was 18.7 and 17.8, respectively. The average heterogeneity-corrected mean doses to the target were 33.75 Gy and 37.94 Gy for the 30-Gy and 34-Gy prescriptions, respectively. Comparing 30-Gy and 34-Gy cohorts, 92.7% and 84.0% of patients, respectively, experienced no toxicity (P was not significant), and had neither grade 3 nor higher toxicities. For the 30-Gy and 34-Gy patients, rates of 1-year local failure, overall survival, and lung cancer-specific mortality were 2.0% versus 13.8%, 75.0% versus 64.0%, and 2. 1% versus 16.0%, respectively (P values for differences were not significant)., Conclusions: This is the largest single-fraction lung SBRT series yet reported. and it confirms the safety, efficacy, and minimal toxicity of this schedule for inoperable early stage lung cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To identify factors associated with grade ≥3 treatment related late esophageal toxicity after lung or liver stereotactic body radiation therapy (SBRT)., Methods and Materials: This was a retrospective review of 52 patients with a planning target volume within 2 cm of the esophagus from a prospective registry of 607 lung and liver SBRT patients treated between 2005 and 2011. Patients were treated using a risk-adapted dose regimen to a median dose of 50 Gy in 5 fractions (range, 37.5-60 Gy in 3-10 fractions). Normal structures were contoured using Radiation Therapy Oncology Group (RTOG) defined criteria., Results: The median esophageal point dose and 1-cc dose were 32.3 Gy (range, 8.9-55.4 Gy) and 24.0 Gy (range, 7.8-50.9 Gy), respectively. Two patients had an esophageal fistula at a median of 8.4 months after SBRT, with maximum esophageal point doses of 51.5 and 52 Gy, and 1-cc doses of 48.1 and 50 Gy, respectively. These point and 1-cc doses were exceeded by 9 and 2 patients, respectively, without a fistula. The risk of a fistula for point doses exceeding 40, 45, and 50 Gy was 9.5% (n=2/21), 10.5% (n=2/19), and 12.5% (n=2/16), respectively. The risk of fistula for 1-cc doses exceeding 40, 45, and 50 Gy was 25% (n=2/9), 50% (n=2/4), and 50% (n=2/4), respectively. Eighteen patients received systemic therapy after SBRT (11 systemic chemotherapy, and 6 biologic agents, and 1 both). Both patients with fistulas had received adjuvant anti-angiogenic (vascular endothelial growth factor) agents within 2 months of completing SBRT. No patient had a fistula in the absence of adjuvant VEGF-modulating agents., Conclusions: Esophageal fistula is a rare complication of SBRT. In this series, fistula was seen with esophageal point doses exceeding 51 Gy and 1-cc doses greater than 48 Gy. Notably, however, fistula was seen only in those patients who also received adjuvant VEGF-modulating agents after SBRT. The potential interaction of dose and adjuvant therapy should be considered when delivering SBRT near the esophagus., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Recent studies with two fractionation schemes predicted that the volume of chest wall receiving >30 Gy (V30) correlated with chest wall pain after stereotactic body radiation therapy (SBRT) to the lung. This study developed a predictive model of chest wall pain incorporating radiobiologic effects, using clinical data from four distinct SBRT fractionation schemes., Methods and Materials: 102 SBRT patients were treated with four different fractionations: 60 Gy in three fractions, 50 Gy in five fractions, 48 Gy in four fractions, and 50 Gy in 10 fractions. To account for radiobiologic effects, a modified equivalent uniform dose (mEUD) model calculated the dose to the chest wall with volume weighting. For comparison, V30 and maximum point dose were also reported. Using univariable logistic regression, the association of radiation dose and clinical variables with chest wall pain was assessed by uncertainty coefficient (U) and C statistic (C) of receiver operator curve. The significant associations from the univariable model were verified with a multivariable model., Results: 106 lesions in 102 patients with a mean age of 72 were included, with a mean of 25.5 (range, 12-55) months of follow-up. Twenty patients reported chest wall pain at a mean time of 8.1 (95% confidence interval, 6.3-9.8) months after treatment. The mEUD models, V30, and maximum point dose were significant predictors of chest wall pain (p < 0.0005). mEUD improved prediction of chest wall pain compared with V30 (C = 0.79 vs. 0.77 and U = 0.16 vs. 0.11). The mEUD with moderate weighting (a = 5) better predicted chest wall pain than did mEUD without weighting (a = 1) (C = 0.79 vs. 0.77 and U = 0.16 vs. 0.14). Body mass index (BMI) was significantly associated with chest wall pain (p = 0.008). On multivariable analysis, mEUD and BMI remained significant predictors of chest wall pain (p = 0.0003 and 0.03, respectively)., Conclusion: mEUD with moderate weighting better predicted chest wall pain than did V30, indicating that a small chest wall volume receiving a high radiation dose is responsible for chest wall pain. Independently of dose to the chest wall, BMI also correlated with chest wall pain., (Copyright © 2012 Elsevier Inc. All rights reserved.)