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Purpose Preclinical data and subset analyses from immunotherapy clinical trials indicate that prior radiation therapy was associated with better progression-free survival and overall survival when combined with immune checkpoint inhibitors in patients with non-small cell lung cancer. We present a prospective study of hypofractionated image guided radiation therapy (HIGRT) to a single site of metastatic disease concurrently with atezolizumab in patients with metastatic non-small cell lung cancer. Methods and Materials Patients meeting eligibility criteria received 1200 mg of atezolizumab intravenously every 3 weeks with concurrent 3- or 5-fraction HIGRT starting no later than the second cycle. The 3-fraction regimen employed a minimum of 8 Gy per fraction compared with 6 Gy for the 5-fraction regimen. Imaging was obtained every 12 weeks to assess response. Results From October 2015 to February 2017, 12 patients were enrolled in the study (median age 64; range, 55-77 years). The best response by the Response Evaluation in Solid Tumors criteria was partial response in 3 and stable disease in 3, for a disease control rate of 50%. Five patients had a grade 3 immune-related adverse event, including choreoretinitis (n = 1), pneumonitis (n = 1), transaminitis (n = 1), fatigue (n = 1), and peripheral neuropathy (n = 1). The median progression-free survival was 2.3 months, and the median overall survival was 6.9 months (range, 0.4-not reached). There was no clear association between peripheral blood T cell repertoire characteristics at baseline, PD-L1, or tumor mutations and response or outcome. One long-term survivor exhibited oligoclonal T cell populations in a baseline tumor biopsy that were consistently detected in peripheral blood over the entire course of the study. Conclusions HIGRT plus atezolizumab resulted in an overall response rate of 25% and disease control rate of 50% in this pilot study. The incidence of grade 3 adverse events was similar to that of atezolizumab alone. Alhough it was a pilot study with limited sample size, the results generated hypotheses worthy of further investigation.

Purpose To assess the utility of circulating serum microRNAs (c-miRNAs) to predict response to high-dose radiation therapy for locally advanced non-small cell lung cancer (NSCLC). Methods and Materials Data from 80 patients treated from 2004 to 2013 with definitive standard- or high-dose radiation therapy for stages II-III NSCLC as part of 4 prospective institutional clinical trials were evaluated. Pretreatment serum levels of 62 miRNAs were measured by quantitative reverse transcription–polymerase chain reaction array. We combined miRNA data and clinical factors to generate a dose–response score (DRS) for predicting overall survival (OS) after high-dose versus standard-dose radiation therapy. Elastic net Cox regression was used for variable selection and parameter estimation. Model assessment and tuning parameter selection were performed through full cross-validation. The DRS was also correlated with local progression, distant metastasis, and grade 3 or higher cardiac toxicity using Cox regression, and grade 2 or higher esophageal and pulmonary toxicity using logistic regression. Results Eleven predictive miRNAs were combined with clinical factors to generate a DRS for each patient. In patients with low DRS, high-dose radiation therapy was associated with significantly improved OS compared to treatment with standard-dose radiation therapy (hazard ratio 0.22). In these patients, high-dose radiation also conferred lower risk of distant metastasis and local progression, although the latter association was not statistically significant. Patients with high DRS exhibited similar rates of OS regardless of dose (hazard ratio 0.78). The DRS did not correlate with treatment-related toxicity. Conclusions Using c-miRNA signature and clinical factors, we developed a DRS that identified a subset of patients with locally advanced NSCLC who derive an OS benefit from high-dose radiation therapy. This DRS may guide dose escalation in a patient-specific manner.

We aimed to report the final toxicity results on a radiation-dose escalation trial designed to test a hypothesis that very high doses of radiation could be safely administered to patients with non-small-cell lung cancer (NSCLC) by quantifying the dose-volume toxicity relationship of the lung.A total of 109 patients with unresectable or medically inoperable NSCLC were enrolled and treated with radiation-dose escalation (on the basis of predicted normal-lung toxicity) either alone or with neoadjuvant chemotherapy by use of 3D conformal techniques. Eighty-four patients (77%) received more than 69 Gy, the trial was stopped after the dose reached 103 Gy. Estimated median follow-up was 110 months.There were 17 (14.6%) Grade 2 to 3 pneumonitis and 15 (13.8%) Grade 2 to 3 fibrosis and no Grade 4 to 5 lung toxicity. Multivariate analyses showed them to be (1) not associated with the dose prescribed to the tumor, and (2) significantly (p0.001) associated with lung-dosimetric parameters such as the mean lung dose (MLD), volume of lung that received at least 20 Gy (V20), and the normal-tissue complication probability (NTCP) of the lung. If cutoffs are 30% for V20, 20 Gy for MLD, and 10% for NTCP, these factors have positive predictive values of 50% to 71% and negative predictive value of 85% to 89%.With long-term follow-up for toxicity, we have demonstrated that much higher doses of radiation than are traditionally administered can be safely delivered to a majority of patients with NSCLC. Quantitative lung dose-volume toxicity-based dose escalation can form the basis for individualized high-dose radiation treatment to maximize the therapeutic ratio in these patients.

Purpose To test whether radiation-induced elevations of transforming growth factor-β1 (TGF-β1) during radiation therapy (RT) correlate with radiation-induced lung toxicity (RILT) in patients with non-small-cell lung cancer (NSCLC) and to evaluate the ability of mean lung dose (MLD) to improve the predictive power. Methods and Materials Eligible patients included those with Stage I–III NSCLC treated with RT with or without chemotherapy. Platelet-poor plasma was obtained pre-RT and at 4–5 weeks (40–50 Gy) during RT. TGF-β1 was measured using an enzyme-linked immunosorbent assay. The primary endpoint was ≥ Grade 2 RILT. Mann-Whitney U test, logistic regression, and chi-square were used for statistical analysis. Results A total of 165 patients were enrolled in this study. The median radiation dose was 60 Gy, and the median MLD was 15.3 Gy. Twenty-nine patients (17.6%) experienced RILT. The incidence of RILT was 46.2% in patients with a TGF-β1 ratio > 1 vs. 7.9% in patients with a TGF-β1 ratio ≤ 1 ( p 20 Gy vs. 17.4% if MLD ≤ 20 Gy ( p = 0.024). The incidence was 4.3% in patients with a TGF-β1 ratio ≤ 1 and MLD ≤ 20 Gy, 47.4% in those with a TGF-β1 ratio >1 or MLD > 20 Gy, and 66.7% in those with a TGF-β1 ratio >1 and MLD > 20 Gy ( p Conclusions Radiation-induced elevation of plasma TGF-β1 level during RT is predictive of RILT. The combination of TGF- β1 and MLD may help stratify the patients for their risk of RILT.

Purpose: To determine whether high-dose radiation leads to improved outcomes in patients with non–small-cell lung cancer (NSCLC). Methods and Materials: This analysis included 106 patients with newly diagnosed or recurrent Stages I–III NSCLC, treated with 63–103 Gy in 2.1-Gy fractions, using three-dimensional conformal radiation therapy (3D-CRT) per a dose escalation trial. Targets included the primary tumor and any lymph nodes ≥1 cm, without intentionally including negative nodal regions. Nineteen percent of patients (20/106) received neoadjuvant chemotherapy. Patient, tumor, and treatment factors were evaluated for association with outcomes. Estimated median follow-up was 8.5 years. Results: Median survival was 19 months, and 5-year overall survival (OS) was 13%. Multivariate analysis revealed weight loss ( p = 0.011) and radiation dose ( p = 0.0006) were significant predictors for OS. The 5-year OS was 4%, 22%, and 28% for patients receiving 63–69, 74–84, and 92–103 Gy, respectively. Although presence of nodal disease was negatively associated with locoregional control under univariate analysis, radiation dose was the only significant predictor when multiple variables were included ( p = 0.015). The 5-year control rate was 12%, 35%, and 49% for 63–69, 74–84, and 92–103 Gy, respectively. Conclusions: Higher dose radiation is associated with improved outcomes in patients with NSCLC treated in the range of 63–103 Gy.

2. The binary logistic regression analysis:  Pericardium V50 was positively associated with PCE; while the age, hypertension were negatively with the PCE. • The mean, maximum dose, and V5-V65 for heart were not significantly related to PCE. 3. The cox regression analysis:  Pericardium V55 was positively associated with survival; while the radiation tumor dose was negatively with the survival. • The mean, maximum dose, and V5-V65 for heart were not significantly related to survival.

Purpose/Objective(s): A recent analysis from 7 RTOG trials suggested that patients treated more than 63 Gy in 1.8 - 2 Gy fractions was significantly associated with better outcome. This study aims to examine whether higher dose (.70 Gy) through personalized prescription can further improve local regional tumor control and overall survival, particularly in patients treated with concurrent chemotherapy. Materials/Methods: This is a secondary analysis of prospective trials from one single Institution. Patients received a definitive dose of fractionated RT, enrolled in imaging and treatment trials, with a minimum follow-up of 6 months were eligible. For the imaging trial,subjectswere treated per standard practice(60 - 70Gy) with or without concurrentchemotherapy basedon the stage of the diseases. For the treatment protocol, all subjects had an opportunity of receiving individualized higher dose RT based on the timing of treatment, and dosimetry of OARs (mainly the normal tissue complication probability of both lungs). Tumor local regional and distant progression free and overall survival (LRPFS, DPFS, and OS) were computed for tumor control outcome assessment. Results: A total of 85 consecutive patients treated between 2004 and 2010 were eligible. The median physical dose was 70 Gy (range60-86Gy)in2to3.8Gydailyfractionations.MinimumFUforsurvivalptswas6months.TheRTdosesweresignificantly associated with LRPFS,DPFS and OS,with hazard ratios of 0.92 (P=0.001),0.94 (P=0.016) and 0.91 (P=0.001),respectively. The median LRPFS (95%CI) was 9.9 (7.5, 12.4) and not reached (not reached) months (P\0.001), for PD\and .70 Gy, respectively. In patients with ‘‘no’’ chemotherapy, median LRPFS was 8.3 (5.8, 10.8) and not reached (P =0.2), for PD\70 Gy and.70 Gy, respectively. For patients treated with concurrent chemotherapy, median LRPFS was 10.7 (8.4, 13.0) months and not reached (not reached) months (P = 0.001), for PD\70 Gy and .70 Gy, respectively. The median OS (95%CI) was 18.2 (10.9, 25.4) and 41.9 (20.6, 63.1) months (P = 0.003), for PD\and .70 Gy, respectively. In those with ‘‘no’’ chemotherapy, median OS was 18.2 (0, 38.6) and not reached (P = 0.443), for PD\70 Gy and .70 Gy, respectively. For patients treated with concurrent chemotherapy, median survival was 15.5 (6.5 - 24.4) and 41.9 (18.3 - 65.5) months (P = 0.003), for PD\70 Gy and .70 Gy, respectively. Using 74 Gy PD (75 percentile of dose) as a cut-off, the median OS and LRPFS were also significantly better in the higher dose group (\74 Gy vs. $ 74 Gy). Conclusions: High dose (.70 Gy) RT improves local regional tumor control and overall survival in patients with and without concurrent chemotherapy. Randomized trials are needed to validate this promising result.