Locally Advanced Non-small Cell Lung Cancer Research Articles

Treatment strategies for unresectable locally advanced non-small cell lung cancer in the real-life ESME cohort

BackgroundCisplatin-based chemotherapy administered concurrently to thoracic radiation therapy is the recommended treatment for fit patients with unresectable stage III NSCLC. The aim of this study was to describe patient profiles and clinical outcomes for the different treatment strategies in a real-word setting. MethodsThe epidemio-strategy and medical economics (ESME) database for advanced and metastatic lung cancer is a French, national, multicenter, observational cohort. Out of 8514 Patients, 822 patients with unresectable locally advanced NSCLC in 2015-016 were selected (mean age, 65.3 years; male gender, 69%; performance status 0–1, 77%; smokers or former smokers, 89%). ResultsTreatment was initiated for 736 (90%) of patients (concurrent chemoradiotherapy, n = 283; sequential chemoradiotherapy, n = 121; chemotherapy alone, n = 194; radiotherapy alone, n = 121; targeted therapy alone, n = 8; other, n = 9). Compared to the other treatment strategy groups, patients with radiotherapy alone appeared the most fragile (e.g. higher age, lower body weight or higher frequency of chronic obstructive pulmonary disease). OS rates at 12 and 24 months were 79.5% (95% CI, 73.4–84.3) and 55.3% (95% CI, 44.9–64.5) for concurrent chemoradiotherapy, and 64.3% (95% CI, 52.8–73.8) and 53.2 (95% CI, 33.2–69.6) for sequential chemoradiotherapy. ConclusionsReal-world evidence shows that concurrent chemoradiotherapy is administered to the most fit patients with non resectable locally-advanced NSCLC. Clinical outcomes are actually higher than those reported in landmark clinical trials, which suggests that an optimized and individualized selection of patients allows for prolonged survival. Long-term outcomes are similar after sequential or concurrent chemoradiotherapy.

Circulating Tumor DNA Dynamics Predict Prognosis of Locally Advanced Non-Small Cell Lung Cancer Patients Treated With Definitive Chemoradiotherapy

Locally advanced non-small cell lung cancer (LA-NSCLC) has strong tumor heterogeneity. Postradiotherapy concentration of circulating tumor DNA (ctDNA) has been demonstrated a promising prognostic biomarker of LA-NSCLC and might be helpful in assisting consolidation decision-making. However, it is widely acknowledged that many biomarkers are specific to certain patient populations. Therefore, we performed this prospective study in Chinese patients with LA-NSCLC to evaluate the prognostic role of ctDNA.We consecutively enrolled patients with unresectable LA-NSCLC. Plasma samples were prospectively collected at different time point if obtained (1) baseline (pretreatment), (2) the fourth week during radiotherapy (RT), and (3) one-month post RT. All plasma specimens were subjected to next-generation sequencing panel of 474 cancer-related genes. Plasma samples with at least 1 variant detected were defined as ctDNA+. A landmark analysis was used to assess predictive value of ctDNA clearance at the time point of one-month post RT. Nonparametric test was used to compare ctDNA concentrations among groups. The Kaplan-Meier method was used to estimate survival distributions, Cox model to estimate hazard ratios and confidence intervals, and log-rank test to estimate P value.A total of 35 patients treated with definitive chemoradiotherapy (CRT) were enrolled. The median follow-up from diagnosis was 16 months. At baseline timepoint, 21 patients with ctDNA+ and 14 patients with ctDNA-. For ctDNA+ patients, ctDNA concentration (ng/ml) was significantly higher with increasing clinical stage (stage IIIA vs stage IIIB vs stage IIIC, 0.345 vs 0.580 vs 3.630, P = 0.007). Both progression free survival (PFS) and overall survival (OS) was not significantly different between ctDNA- and ctDNA+ group at baseline timepoint. However, at the time point of one-month post RT, patients with ctDNA- had significantly higher PFS (median: NA vs 7 months; HR 0.205, 95% CI: 0.066∼0.637; P = 0.002) and OS (HR 0.065, 95% CI: 0.008∼0.541; P = 0.001). Kinetic changes in ctDNA concentrations were analyzed in 16 pts with matching baseline and one-month post RT specimens. Of these 16 cases with detectable ctDNA at baseline, 50% (8/16) became undetectable at one-month post RT ("ctDNA clearance"), all these 8 patients were alive and nonrecurrent during the following-up. ctDNA clearance was associated with significantly higher PFS (P = 0.003) and OS (P = 0.016) compared with ctDNA residual patients.For LA-NSCLC receiving CRT, ctDNA concentration was significantly higher with increasing clinical stage (IIIA vs IIIB vs IIIC). Baseline ctDNA+/- seemed not a prognosis factor, whereas ctDNA- or ctDNA clearance at the time of one-month post RT was associated with significantly superior PFS and OS. More enrolled patients are needed to update and validate these results.NCT04014465.

Are Advanced Radiation Techniques Safe to Use in Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC)? Analysis Based on Pathologic Regression and Local Recurrence

VMAT, deep inspiratory breath hold (DIBH) and adaptive replanning (ART), are increasingly used for LA-NSCLC to improve conformality and reduce treatment toxicity. Yet, impact of these advanced techniques on pathologic response (PR) and local recurrence (LR) is lacking. We evaluated VMAT, DIBH and ART compared to 3D-conformal radiation therapy (3DCRT) and free breathing (FB), hypothesizing that PR and LR would be unaffected.Retrospective analysis of PR and LR in patients with LA-NSCLC treated in a single academic center between 2012-2021 with platinum based chemoradiation (CRT) followed by completion resection. Radiation techniques assessed: VMAT, DIBH and ART (due to tumor shrinkage during treatment).gender, smoking, stage, GTV, tumor histology, tumor location, dose (Gy), chemotherapy, and time interval between CRT and surgery.PR and LR. PR was converted to a binary variable: Major pathologic regression (MPR) (complete response or ≤10% residual tumor cells) vs. residual tumor (> 10% residual tumor cells). Pathological assessment was blinded to radiation technique. LR was determined by CT or PET-CT. Statistical analysis was by logistic regression.Characteristics of patients (n = 106) with LA-NSCLC were: median age: 63 (range 43-79), males: 73/106 (69%), mean radiation dose: 60.7 Gy (SD 4.6 Gy), median GTV: 115cc (range 19-448), and median time interval (CRT-surgery): 65d (range 28-424d). Radiation techniques were: 3DCRT-FB (n = 51, 48 %), VMAT-FB (n = 40, 38%), VMAT-DIBH (n = 15, 14%), and ART (n = 24, 22.6%). Overall MPR was 73/106 (68.9%). MPR was not significant for VMAT (40/55, 73%) vs. 3DCRT (33/51, 64.7%) (OR 0.7, NS) or DIBH (11/15, 73%) vs. FB (62/91, 68%) (OR-1.1, NS). MPR was significant for ART (20/24, 83%) vs. no-ART (53/82, 64.6%) (OR 3.2, P = 0.037), never smokers (6/18, 33%) vs. smokers (65/86, 75%) (OR-0.49, P = 0.007), GTV > 115cc (45/55, 81%) vs. GTV ≤115 cc (28/51, 55%) (OR-0.27, P = 0.007), and time interval between CRT and surgery > 66 d (44/53, 83%) vs. time interval ≤ 65 d (29/53, 55%) (OR-0.2, P = 0.002). The following variables did not corelate with MPR: age, gender, histology, stage, lower lobe location, chemotherapy type and dose > 60 Gy. LR occurred in 17/106 patients. LR trended lower with: ART (1/24, 4%) vs. no ART (16/81, 20%) (HR 1.25 P = 0.7), DIBH (1/15, 6.7%) vs. FB (16/90, 17.8%) (HR-0.86, P = 0.7), and VMAT (6/54, 11%) vs. 3D CRT (11/51, 21%) (HR 0.7, P = 0.6).Pathologic and radiographic comparisons show use of VMAT, DIBH and ART in LA-NSCLC did not adversely influence pathologic regression or LR. Use of ART was associated with increased MPR and reduced LR. GTV, smoking status and time interval between CRT and surgery were associated with MPR. Further investigation of these variables is planned.

Diagnostic Signatures for Lung Cancer by Gut Microbiome and Urine Metabolomics Profiling

<h3>Purpose/Objective(s)</h3> To develop the diagnostic signatures for lung cancer (LC) by gut microbiome and urine metabolomics profiling with multi-omics approach. Additionally, to investigate the predictive role of gut microbiome on the prognosis of locally advanced non-small cell lung cancer (LANSCLC) patients after concurrent chemoradiotherapy (CCRT). <h3>Materials/Methods</h3> Fecal and urine samples were collected in LC patients and healthy individuals. The total cohort had been divided into the training set (47 patients and 20 healthy individuals) and the validation set (48 patients and 30 healthy individuals) for multi-omics analysis. Gut microbiota was analyzed through the 16S ribosomal RNA gene sequencing and shotgun metagenomics. Urine untargeted metabolomics was analyzed by liquid chromatography-mass spectrometry. Multi-omics diagnostic model incorporating features from fecal microbiome and urine metabolites was developed in the training set, and then validated in the validation set. Among them, 36 patients with LANSCLC were selected for prognosis analysis, with fecal samples collected at three longitudinal time points (baseline, 2 weeks after the start of CCRT and the end of CCRT). These patients were divided into 2 groups according to progression-free survival (PFS) (PFS > = 12 months [LP], n = 14; PFS < 12 months [SP], n = 22). The microbiome profiling of LP and SP were compared using Wilcoxon rank-sum test. <h3>Results</h3> LC patients had a significant shift of microbiota composition and functional genes distribution compared with healthy individuals. Diagnostic model for LC had been achieved by combining gut microbiome and urine metabolomics profiling, the area under curve (AUC) of the training set was 0.9997, and 0.9769 for the validation set. We also found a significant decrease of Prevotella in LC patients and it was negatively correlated with multiple functions in KEGG level 2. For the 36 patients with LANSCLC who had underwent CCRT, the alpha diversity was significantly increased in LP group compared with SP group at 2 weeks after CCRT (Chao1: <b>P</b> = 0.013, PD: <b>P</b> = 0.037, Shannon: <b>P</b> = 0.011). Further analysis of microbiota composition identified 21 differentially abundant species (<b>P</b> < 0.05). 19 and 2 species were LP-enriched and SP-enriched, respectively. 5 Lachnospiraceae genus, 3 Eubacterium genus were significantly enriched in LP group, while Prevotellaceae and Lactobacillus were significantly enriched in SP group. <h3>Conclusion</h3> The current study employed a multi-omics approach, analyzed the fecal microbiome and urine metabolites from LC patients using a standardized pipeline, and identified disease-associated microbiome shifts across datasets using statistical analysis. We inferred a microbiome-metabolite catalog and its molecular pathway and functional link to host targets, which could be further utilized to aid lung cancer diagnosis and treatment decision. Furthermore, gut microbiota at 2 weeks after the start of CCRT might have a predictive role on the prognosis of NSCLC after CCRT.

A Phase II Trial of Primary Tumor SBRT Boost Prior to Concurrent Chemoradiation for Locally-Advanced Non-Small Cell Lung Cancer (LA-NSCLC)

Primary tumor failure is common in patients treated with chemoradiation (CRT) for unresectable LA-NSCLC. Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control in Stage I NSCLC. This trial tested an SBRT boost to the primary tumor prior to the start of CRT to improve primary tumor control (PTC).Patients with LA-NSCLC with primary tumor ≤10 cm were enrolled on a prospective phase II trial testing an SBRT boost in 2 fractions (central 6 Gy x 2, peripheral 8 Gy x 2) immediately followed by standard concurrent CRT (60 Gy in 30 fractions). Patients were staged with PET-CT, brain MRI, and underwent 4D-CT simulation for radiation planning using a customized immobilization device that enabled radiation planning for the sequential delivery of the SBRT boost and conventionally-fractionated radiation from the same CT dataset. Chemotherapy was carboplatin/paclitaxel (C/P) or cisplatin/etoposide. For patients receiving C/P, consolidation C/P for 2 cycles was given at the discretion of the medical oncologist. The trial was later amended to allow for consolidation durvalumab. The primary objective was to estimate PTC rate at 1-year with a hypothesis that the 1-year PTC rate is ≥90%. Secondary objectives were to establish the safety, feasibility, objective response rate (ORR; RECISTv1.1), and rates of regional & distant control, disease-free survival (DFS), and overall survival (OS). Exploratory functional MRI (fMRI) scans before and within the first 30 hrs of the first SBRT fraction were performed in 11 patients.The study enrolled 21 patients (10 male, 11 female), with median age 62 years (range 52-78). 16 patients received 6 Gy x 2 SBRT boost, while 5 patients received 8 Gy x 2 SBRT boost. 18 patients received C/P chemotherapy, of whom 9 patients received consolidation C/P. Six patients received consolidation durvalumab. Median pre-treatment primary tumor size was 5.0 cm (range 1.0-8.3). Median and mean follow-up were17.9 and 20.2 months, respectively. The most common toxicities were fatigue, neutropenia, leukopenia, lymphopenia, anemia, pneumonitis, fibrosis, dyspnea and esophagitis. Five grade 4 toxicities related to treatment occurred [lymphopenia (3), neutropenia (1), and leukopenia (1)], but no grade 5 toxicities related to treatment occurred. ORR at 3 and 6 months was 72.7% and 80.0%. The PTC rate was 100% and 92.3% at 1 and 2 years, respectively. The 2-year regional and distant control were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 yrs were 46.1% and 50.3%, respectively. Median survival was 37.8 months. fMRI detected a mean relative decrease in BOLD signal of -87.1% (P = 0.05).Dose escalation to the primary tumor utilizing upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably with the literature. Through the use of 1 CT simulation dataset, accurate calculation of the planned dose through the 2 sequentially-delivered plans is achievable.

Pre-Treatment Immune-Related Markers Predict Disease Outcomes in Non-Small Cell Lung Cancer Patients Treated With Chemoradiation and Durvalumab

Immune-related markers from the peripheral blood and radiation dose to the immune system have been associated with outcomes in locally-advanced non-small cell lung cancers (LA-NSCLC) patients treated with concurrent chemoradiation (cCRT). We assessed if the neutrophil-to-lymphocyte ratio (NLR), and risk scores from two dose models (Estimated Dose of Radiation to Immune Cells (EDRIC) and the RTOG 0617 overall survival (OS) model including cardiopulmonary dose) are also associated with outcomes in patients treated with cCRT and durvalumab.Consecutive LA-NSCLC patients treated with platinum-based cCRT and at least one dose of durvalumab between November 2017 and December 2019 were evaluated. The pre-cCRT and pre-durvalumab NLR were calculated using samples most proximal to RT and durvalumab start (NLRpre-cCRT, NLRDurvalumab). Mean body dose, mean heart dose and mean lung dose (MLD) were extracted to calculate EDRIC; atria D45, mean of the hottest 5% of the ventricle dose (MOH5), pericardium MOH55 and MLD were used to calculate OS risk scores from the 0617 model. Progression-free survival (PFS) was defined from the start of cCRT. NLRpre-cCRT, NLRDurvalumab, risk scores from the two dose models, and patient characteristics (stage, age, PD-L1, ECOG status) were associated with PFS using bootstrapped Cox proportional hazards modeling. A Bonferroni-corrected P≤0.006 was considered statistically significant.A total of 105 patients with a median follow-up of 20 months (IQR: 13-27) were included. Median age was 67 years, 60% were male, and 45% were ECOG 1. Most patients had adenocarcinoma histology (n = 64) and stage IIIB/IIIC disease (n = 71). PD-L1 expression was available for 75% of patients, of which 66% had PD-L1 expression ≥1%. Patients were treated with a median of 7 (IQR: 2-12) months of durvalumab that started a median of 7 (5-9) weeks from end of cCRT. Twenty-eight (27%) patients discontinued durvalumab due to toxicity after a median of 2 (IQR: 1-4) months. In total, 41 patients had a progression event at a median of 8 (IQR: 6-11) months. The 12- and 18-months PFS estimates were 69% (95% CI: 60-78%) and 62% (52-72%), respectively. The median NLRpre-cCRT was 3.4 (IQR: 2.2-4.7), NLRDurvalumab was 5.5 (IQR: 3.6-7.4). The median risk score for EDRIC was 5.3 (IQR: 3.9-6.6) and 0.82 (IQR: 0.62-1.1) for the 0617 model. Among the investigated variables only NLRpre-cCRT reached significance in predicting PFS (HR: 1.10, 95% CI 1.05-1.16, P = 0.0002). Further, NLRpre-cCRT was not strongly correlated with age, stage, PD-L1 expression or ECOG status (Spearman's rho range: -0.22, 0.22).This study represents the first effort focusing on immune-related markers and dose models in LA-NSCLC treated with cCRT and durvalumab and finds the pre-cCRT NLR as the best predictor of disease outcomes.

Cardiac Radiation Dose and Patient Risk Factors for Predicting Major Adverse Cardiac Events in Lung Cancer Patients

<h3>Purpose/Objective(s)</h3> Thoracic radiotherapy (TRT) is a mainstay treatment for locally advanced non-small cell lung cancer (LA-NSCLC). Mean heart dose (MHD) and left anterior descending (LAD) receiving ≥15 Gy (LADV15) was shown to predict major adverse cardiac events (MACE) in LA-NSCLC patients receiving TRT. We aim to develop a clinically applicable MACE risk prediction score model, including both cardiac dosimetric and baseline risk factors. <h3>Materials/Methods</h3> Retrospective data from 748 consecutive patients with LA-NSCLC treated with curative intent between November 1998 to December 2013 were included. The data was split based on diagnosis dates to allow external validation. Model development was performed on 500 consecutive patients diagnosed before December 2010 using multivariable Cox-proportional hazard model; backward elimination scheme (α = 0.05) was used to select the predictors for the final model. Potential predictors were selected <b>a priori</b> based on prior literature: age, pre-existing coronary heart disease (CHD), Framingham Risk, hypertension (HTN), MHD, LADV15, intensity modulated RT (IMRT) use, and interaction between CHD and LADV15 (CHD:LADV15). Model performance was assessed by the Harrell's c-index and internally validated using leave-one out cross validation (LOOCV). The model was applied to the remaining 248 consecutive patients from the initial cohort as the external validation "test" dataset. <h3>Results</h3> The development and test cohorts had median age 64 vs 66 years (<i>P</i> = 0.02), 51.0 vs. 50.4% females (<i>P</i> = 0.88), and 89.4 vs 89.1% stage III cancer (<i>P</i> = 0.91). The final model incorporated CHD, HTN, LADV15, and CHD:LADV15 (β coefficients: 2.703, 1.129, 0.043, -0.047; all <i>P</i> < 0.001; c-index 0.773). LOOCV Pseudo R² = 0.0195. The c-index on the external test dataset was 0.727. Actuarial 3-year MACE rates were 10.7% for development cohort and 15.4% for test cohort. Stratifying development cohort patients into terciles based on MACE risk prediction scores yielded 3-year MACE rates of 0%, 5.7%, and 25.6% for lowest to highest risk-terciles, respectively; among test cohort, the 3-year MACE rates were 4.9%, 10.5%, and 31.9%. Respectively, the 3-year overall survival rates for lowest to highest MACE risk-terciles were 47.3%, 35.2%, and 32.8% among development cohort, and 52.3%, 43.9% and 30.6% within test cohort (both Log-rank <i>P</i> < 0.05). <h3>Conclusion</h3> The 3-year MACE rates spans 5% to 32% from lowest to highest risk groups. Both LADV15 and pre-existing cardiac risk factors are important in predicting MACE risk post-TRT. MACE risk score was associated with survival. This tool has the potential to estimate personalized LADV15 constraints based on patient risk factors and acceptable MACE risk thresholds (e.g., 5-10%), thus may help identify patients who may benefit most from the application of advanced RT techniques to further reduce LAD dose as a modifiable risk factor during RT planning.

Efficacy and Safety of Thoracic Radiotherapy in Locally Advanced Non-Small Cell Lung Cancer Patients With Pre-Existing Interstitial Lung Diseases: A Single Center Experience of 85 Cases

<h3>Purpose/Objective(s)</h3> Whether thoracic radiotherapy (TRT) could be applied to interstitial lung diseases and lung cancer (ILD-LC) patients safely remains unclear. This retrospective study aims to evaluate the efficacy and safety of definitive TRT in locally advanced non-small cell lung cancer (LA-NSCLC) patients with pre-existing ILD, and to analyze the associated risk factors for radiation induced lung toxicities (RILTs) in the clinical setting. <h3>Materials/Methods</h3> Patients with histologically confirmed LA-NSCLC and pre-existing ILD treated definitive TRT between 2010 and 2019 were retrospectively reviewed. Patient, tumor, and treatment characteristics were evaluated to determine the risk factors for RILTs. Pre-radiation CT of all patients were reviewed by two radiologists and one pulmonologist and are scored according to Müller's thin-section CT scoring system for IPF: 0-no discrete honeycombing, with interlobular septal thickening; 1-honeycombing involving 0-5% of the lobe; 2-honeycombing 6-24%; 3-honeycombing 25-49%; 4-honeycombing 50-74%;5-honeycombing > 75%. Univariate and multivariate analyses with logistic regression models and cox proportional hazards approach were performed to identify the risk factor(s) of RILTs and overall survival (OS) respectively. <h3>Results</h3> Among 1261 LA-NSCLC patients, 85 were found with pre-existing ILD and enrolled in the analysis. 36.5% of them were scored more than 1 point on CT. 20% patients developed G3+ RILTs within 1 year after the last irradiation, with remarkably 11.8% dying from lung toxicities. And the incidence of symptomatic (G3+) RILTs abruptly dropped to 11.1% (6/54), 3.8% (1/26), and 0% (0/19) for patients with CT score ≤1, V20 < 20%, or neither, respectively. Multivariate analysis showed that CT score > 1 and V20 ≥ 20% were independently associated with higher risk of G3+ RILTs. The median OS and PFS were 14.0 months and 7.4 month respectively. In the univariate analysis for OS, clinical stage and G3+RILT were evaluated as risk factors while patients in low-risk group, defined as honeycombing score < 1 and V20 < 20%, had shown a protective tendency (HR = 0.52, 95% CI: 0.27-1.04, <i>P</i> = 0.063). In multivariate analysis, G3+RILT was the only independent risk factor associated with OS (HR = 2.40, 95% CI: 1.32-4.36, <i>P</i> = 0.004). However, the median OS of low-risk group was quite longer than the whole group (26.5 months versus 14.5 months), indicating that patients at low risk might benefit from thoracic radiation therapy. <h3>Conclusion</h3> Honeycombing score > 1 and V20 ≥ 20% were significantly associated with high incidence of severe lung toxicities, leading to poor survival. However, patients at low risk might benefit from TRT with a considerable overall survival.

Dynamic 18F-FDG Total Body PET Imaging as a Predictive Marker of Induction Chemo-Immunotherapy Followed by Concurrent Chemoradiotherapy Response in Locally Advanced Non-Small Cell Lung Cancer

Purpose/Objective(s)The purpose of this study was to evaluate the efficacy of dynamic 18F-FDG total body PET imaging as a predictive maker of induction chemo-immunotherapy followed by concurrent chemoradiotherapy (CCRT) response in locally advanced non-small cell lung cancer (LA-NSCLC) by a prospective study.Materials/MethodsStage IIIA-IIIC NSCLC patients were prospectively enrolled in a prospective total body PETCT study (NCT04654234, GASTO-1067) and a randomized phase II clinical trial (NCT04085250) between September 2020 and December 2020. Patients underwent a dynamic total-body 18F-FDG PET/CT scan before any treatment, after 2 cycles of induction chemo-immunotherapy (docetaxel + cisplatin + nivolumab), then after CCRT. The primary lung tumor, metastatic regional lymph node and inflammatory lymph node before and after treatment were manually delineated by a nuclear medicine physician and a radiation oncologist. Total Body PET was acquired between 0 – 60 mins after the injection of FDG from the subject's feet. Patients was separated into high dynamic FDG metabolic (H-DFM) group and low DFM(L-DFM) group by the scatter plot of SUV-mean and Ki-mean of baseline scan for primary lung tumor. We compared lesion heterogeneity and different image-derived PET metrics including the metabolic tumor volume (MTV), SUV total lesion glycolysis (SUV-TLG), Patlak-derived influx rate constant (Ki) TLG (Ki-TLG).ResultsFifteen patients completed three scans (before treatment, after induction chemo-immunotherapy, after CCRT). Eight patients were in H-DFM group and 7 in L-DFM group by baseline scan. Patients in H-DFM group had significant decreased levels of MTV (P < 0.001), SUV-TLG (P < 0.001) and Ki-TLG (P < 0.001) both in primary lung tumor and metastatic lymph node by the induction chemo-immunotherapy and CCRT. However, patients in L-DFM group only had a significant reduction of MTV in primary lung tumor (P < 0.05). There was no significant difference in the MTV of metastatic lymph node (P > 0.5), the SUV-TLG (P > 0.5) and Ki-TLG (P > 0.5) of primary lung tumor and metastatic lymph node during the treatment course in L-DFM group.ConclusionPatients in H-DFM group had the better treatment response of induction chemo-immunotherapy and CCRT with significant decreased levels of MTV, SUV-TLG and Ki-TLG. Dynamic 18F-FDG Total body PET Imaging could be regarded as a potential predictive marker of induction chemo-immunotherapy and CCRT response in the setting of LA-NSCLC. The purpose of this study was to evaluate the efficacy of dynamic 18F-FDG total body PET imaging as a predictive maker of induction chemo-immunotherapy followed by concurrent chemoradiotherapy (CCRT) response in locally advanced non-small cell lung cancer (LA-NSCLC) by a prospective study. Stage IIIA-IIIC NSCLC patients were prospectively enrolled in a prospective total body PETCT study (NCT04654234, GASTO-1067) and a randomized phase II clinical trial (NCT04085250) between September 2020 and December 2020. Patients underwent a dynamic total-body 18F-FDG PET/CT scan before any treatment, after 2 cycles of induction chemo-immunotherapy (docetaxel + cisplatin + nivolumab), then after CCRT. The primary lung tumor, metastatic regional lymph node and inflammatory lymph node before and after treatment were manually delineated by a nuclear medicine physician and a radiation oncologist. Total Body PET was acquired between 0 – 60 mins after the injection of FDG from the subject's feet. Patients was separated into high dynamic FDG metabolic (H-DFM) group and low DFM(L-DFM) group by the scatter plot of SUV-mean and Ki-mean of baseline scan for primary lung tumor. We compared lesion heterogeneity and different image-derived PET metrics including the metabolic tumor volume (MTV), SUV total lesion glycolysis (SUV-TLG), Patlak-derived influx rate constant (Ki) TLG (Ki-TLG). Fifteen patients completed three scans (before treatment, after induction chemo-immunotherapy, after CCRT). Eight patients were in H-DFM group and 7 in L-DFM group by baseline scan. Patients in H-DFM group had significant decreased levels of MTV (P < 0.001), SUV-TLG (P < 0.001) and Ki-TLG (P < 0.001) both in primary lung tumor and metastatic lymph node by the induction chemo-immunotherapy and CCRT. However, patients in L-DFM group only had a significant reduction of MTV in primary lung tumor (P < 0.05). There was no significant difference in the MTV of metastatic lymph node (P > 0.5), the SUV-TLG (P > 0.5) and Ki-TLG (P > 0.5) of primary lung tumor and metastatic lymph node during the treatment course in L-DFM group. Patients in H-DFM group had the better treatment response of induction chemo-immunotherapy and CCRT with significant decreased levels of MTV, SUV-TLG and Ki-TLG. Dynamic 18F-FDG Total body PET Imaging could be regarded as a potential predictive marker of induction chemo-immunotherapy and CCRT response in the setting of LA-NSCLC.

A Prospective Phase II Clinical Study of Simultaneous Integrated Boost Radiotherapy on Stage III Local-advanced Non-Small Cell Lung Cancer Patients

In consideration of the results of the RTOG0617 study, researchers began to adopt a prudent policy to high-dose radiotherapy. Based on the assume that radiation dose escalation to the primary tumor can improve local control and therefore producing survival benefits under the condition of limiting the dose to the organ at risk (OAR), we launched the study to evaluate the effect of simultaneous Integrated boost (SIB) radiotherapy implemented on the stage III local-advanced non-small cell lung cancer (LA-NSCLC) patients.42 Patients with stage III LA-NSCLC who were eligible for definite concurrent chemoradiotherapy were prospectively given the radiation regimen of single dose of 2.0Gy for PTV, 2.2Gy for CTV, and 2.4 -2.8Gy for GTV with 25 fractions. Other stage III LA-NSCLC patients retrospectively collected with routinely radiotherapy were matched through PSM. 2 Cycles of platinum based concurrent chemotherapy were carried on patients in both groups. The primary endpoints were progression-free survival (PFS), toxic effects and dose for normal tissues, with the secondary end point of overall survival (OS). The Kaplan-Meier method was used to evaluate PFS and OS, and the Mann-Whitney U test for toxic effects and the dose for normal tissues.The median PFS time was 20.6 vs 9.0 months (P = 0.01), and the median OS was 40.0 vs 24.5 months (P = 0.02) in the SIB group and the control group respectively, all were obviously longer in the SIB group. No significant differences of radiation-related pneumonitis (P = 0.95) and myelosuppression (P = 0.40) have been observed between the two groups, as well as nausea, vomiting, esophagitis and dyspnea. The dose and the radiation-effected volume to the surrounding normal tissues also did not show the tendency of increasement in the SIB group.The results of our research has revealed that the dose escalation did improve the PFS and OS while not increased the dose to the surrounding normal tissues and the occurrence of toxic effects. Simultaneous integrated boost radiotherapy to the primary tumor might be a safe and feasible regimen to improve survival benefit for the stage III LA-NSCLC patients eligible for definite concurrent chemoradiotherapy in the future.

Association of a Deep Learning Estimation of Chest Imaging Age With Survival in Patients With Non-Small Cell Lung Cancers Undergoing Radiation

Recent work has challenged emphasis of chronologic age in cancer treatment decision-making. For patients with non-small cell lung cancer (NSCLC), cardiopulmonary risk histories widely vary, possibly impacting "biologic age." We aimed to apply an externally-derived deep learning model to estimate chest imaging age (ChIA) from digitally reconstructed radiographs (DRRs) created from simulation computed tomography (CT) scans of patients with locally advanced NSCLC (LA-NSCLC). We hypothesized ChIA could serve as a prognostic imaging biomarker in this population.We previously pretrained a Resnet34 convolutional neural network (CNN) to predict chronologic age using normal chest radiographs (CXRs) from public cohorts (CheXpert, NIH, and PadCHEST, n = 24,934). We fine-tuned the CNN to predict ChIA based on time to death using CXRs from 13,657 (25%) patients of the Prostate, Lung, Colorectal and Ovarian Cancer Trial, testing in the remaining 75% (n = 40,967) and the National Lung Screening Trial (n = 5,414). We applied the model to simulation CT DRRs in an institutional cohort of patients with LA-NSCLC receiving lung radiation (Lung-RT, n = 847). Recursive partitioning analysis (RPA) identified a cut point associated with overall survival (OS) in Lung-RT, above which patients were classified ChIA-high. We evaluated association between ChIA and OS using Kaplan-Meier calculations and Cox regression analyses and then validated in the multi-institutional RTOG 0617 trial (n = 460).In Lung-RT, median age was 67 (Range 21-90) years and median ChIA was 67 (Range 57-80) years. In RTOG 0617, median age was 64 (37-83) years, and median ChIA was 66 (52-77) years. Age/ChIA correlation coefficients were 0.29 (95% CI 0.23-0.35, P < 0.001) and 0.32 (95% CI 0.23-0.40, P < 0.001), respectively. Table 1 shows OS after median follow-up in Lung-RT of 56 (95% CI 53-58) months, and in RTOG 0617 of 36 (95% CI 32-37) months. In Lung-RT, adjusting for age, race, and sex, ChIA-high patients had HR 1.22 (95% CI 1.00-1.49, P = 0.049) for OS. In RTOG 0617, adjusting for trial arm, age, gender, race, ethnicity, performance status, histology, and stage, ChIA-high patients had HR 1.41 (95% CI 1.02-1.91, P = 0.037) for OS.Our work validates use of a deep learning CXR-based model to predict ChIA using DRRs created from routine simulation CTs of patients with LA-NSCLC. In an institutional and multi-institutional trial cohort, ChIA-high patients had worse survival than ChIA-low patients, suggesting potential use of ChIA as a prognostic imaging biomarker enabling de-emphasis of chronologic age in treatment decision-making.

Clinical Outcomes After Trimodality Therapy With Dose-Escalated Neoadjuvant Intensity-Modulated Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer

Trimodality therapy (TMT) with preoperative chemoradiation followed by surgical resection is used in the management of locally-advanced non-small cell lung cancer (LA-NSCLC). Traditionally, preoperative radiation doses ≤54 Gy are used due to concerns regarding excess morbidity, but little is known about outcomes and toxicities after TMT with intensity-modulated radiotherapy (IMRT) to higher doses. We investigated whether clinical outcomes were different after TMT with IMRT using less than definitive doses of < 60 Gy and definitive doses ≥60 Gy for LA-NSCLC.We conducted an Institutional Review Board-approved retrospective cohort analysis of patients who received planned TMT using IMRT for LA-NSCLC between 2008 and 2017 at one institution. We recorded clinical and treatment characteristics, pathologic response, and surgical toxicity within 30 days. Toxicity was graded using Common Terminology Criteria for Adverse Events version 5.0. Chi-square or Fisher exact tests were used for categorical variables. Survival outcomes were analyzed by Kaplan-Meier method and log-rank test. Univariate and multivariate analyses were performed using Cox proportional-hazards regression.We identified 46 patients receiving doses < 60 Gy and 30 patients receiving doses ≥60 Gy. Distribution of clinical nodal stage was different between the two groups with more cases of N0 and N3 disease in the higher dose group (P = 0.015), but other factors, including age, comorbidities, clinical stage, and surgical approach, were not different. Rates of R0 resection, pathologic complete response, and postoperative toxicity, including cardiovascular toxicity, post-operative infection, intensive care unit (ICU) admission, and length of hospital stay (LOS), were not significantly different between the two groups. Three patients died within 30 days of surgery with two receiving doses ≥60 Gy. Mean esophageal (24.2 vs. 20.2 Gy, P = 0.029) and lung (16.7 vs. 13.6 Gy, P = 0.005) doses were significantly higher for patients receiving doses ≥60 Gy. With median follow-up of 3.6 years (range: 0.4-11.4), 3-year locoregional recurrence-free survival (78.0% vs. 68.3%) and overall survival (OS) (61.0% vs. 69.4%) was not different between patients receiving < 60 Gy and ≥60 Gy. On multivariate analysis, older age, clinical stage, and LOS > 7 days were significantly associated with decreased OS when controlling for sex, surgical approach, post-operative grade ≥3 toxicity, and mean lung dose.We found no increased rate of post-TMT complications in patients receiving higher doses using IMRT. Survival outcomes or LOS did not differ based on radiation dose, but increased LOS was associated with worse OS. Larger prospective studies are needed to further examine outcomes after IMRT in patients with LA-NSCLC receiving TMT.

The 3-Year Outcome of 3D High-Dose-Rate Brachytherapy in Combination With Regional Metastatic Lymph Nodes Intensity-Modulated Radiotherapy in Peripheral Locally Advanced Non-Small Cell Lung Cancer: A Phase I/II Clinical Trial

To determine the safety, late toxicities and locoregional control of three-dimensional(3D) high-dose-rate (HDR) brachytherapy in combination with regional metastatic lymph nodes intensity-modulated radiotherapy (IMRT) in patients with peripheral locally advanced non-small cell lung cancer (LA-NSCLC).Eligible patients with LA-NSCLC were recruited to this prospective, phase I/II clinical study. The primary lung tumors were treated with the CT-guided interstitial HDR brachytherapy, DT:30Gy/F. The IMRT was applied to the regional positive lymph nodes, DT: 60-70Gy/30-33F/ 6-7W. The concurrent chemotherapy regimens include used Etoposide and cisplatin, the sequential chemotherapy consisted of paclitaxel/pemetrexed + cisplatin/carboplatin. The safety analysis included operational complications and toxicity related to radiotherapy and chemotherapy. Clinical evaluation includes short-term efficacy, survival, and quality of life scores.A total of 83 patients were enrolled in this study. There were 56 males and 27 females, with a median age of 65 years (45-80 years). The median follow-up time was 55 months (32-114 months) up to November 2020. The operational complications included mild pneumothorax (16.8%) and minor hemorrhage around the needle (19.3%). The major toxicity was myelosuppression and gastrointestinal reaction during the concurrent chemoradiotherapy and sequential chemotherapy. The clinical symptoms alleviated after symptomatic supportive treatment. The radiotherapy was completed successfully without grade 4 or more serious acute toxicity. Grade 1 late radiation pneumonitis was found by in 5 patients (6.1%), and only showed imaging changes after radiotherapy. There were 61 patients achieved complete remission, 20 patients achieved partial remission, and 2 patients were in stable disease in the primary tumor, the total response rate was 97.6%. There were 55 patients achieved complete remission, 22 patients achieved partial remission, 5 patients were in stable disease and 1 patient with progressive disease in the positive lymph nodes, the total response rate was 92.8%. The 1-,2-,3-year overall survival rates were 90.6%, 70.6% and 62.4%. The 1-,2-,3-year local control rates were 90.0%,81.0% and 54.5%. The 1-,2-,3-year disease-free survival rates were 68.3%,42.2% and 23.9%. The 1-,2-,3-year metastasis-free survival rates were 73.3%, 50.9% and 39.5%. The patient who treated with 3D interstitial high dose rate brachytherapy has a higher life quality score than the baseline level.3D interstitial high dose rate brachytherapy combined with regional positive lymph node intensity-modulated radiotherapy is safe and feasible for the locally advanced peripheral non-small cell lung cancer, with low adverse reactions, increased the survival, and improved the life quality. But it still needs a phase III randomized controlled trial to investigate its clinical utility and promotion, compared to IMRT.

Surgical complications and clinical outcomes after dose-escalated trimodality therapy for non-small cell lung cancer in the era of intensity-modulated radiotherapy

BackgroundTrimodality therapy (TMT) with preoperative chemoradiation followed by surgical resection is used for locally-advanced non-small-cell lung cancer (LA-NSCLC). Traditionally, preoperative radiation doses ≤54 Gy are used due to concerns regarding excess morbidity, but little is known about outcomes and toxicities after TMT with intensity-modulated radiotherapy (IMRT) to higher doses. MethodsA retrospective analysis of patients who received planned TMT with IMRT for LA-NSCLC at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2008 and 2017 was performed. Clinical and treatment characteristics, pathologic response, and surgical toxicity were assessed. Kaplan-Meier method and log-rank test was used for survival outcomes. Cox proportional-hazards regression was used for multivariable analysis. ResultsForty-six patients received less than definitive doses of <60 Gy and 30 patients received definitive doses ≥60 Gy. Surgical outcomes, pathologic complete response, and postoperative toxicity did not differ significantly between the groups. With median follow-up of 3.6 years (range: 0.4–11.4), three-year locoregional recurrence-free survival (78.0% vs. 68.3%, p = 0.51) and overall survival (OS) (61.0% vs. 69.4%, p = 0.32) was not significantly different between patients receiving <60 Gy and ≥60 Gy, respectively. On multivariable analysis, older age, clinical stage, and length of hospital stay (LOS) >7 days were associated with OS. ConclusionsWith IMRT, there was no increased rate of surgical complications in patients receiving higher doses of radiation. Survival outcomes or LOS did not differ based on radiation dose, but increased LOS was associated with worse OS. Larger prospective studies are needed to further examine outcomes after IMRT in patients with LA-NSCLC receiving TMT.

A Non-Parametric Analysis to Estimate Dose Distributions Associated With High-Risk vs. Low-Risk of Death in RTOG 0617

<h3>Purpose/Objective(s)</h3> Analyses of locally-advanced non-small cell lung cancer (LA-NSCLC) series have identified radiation dose to the cardio-pulmonary system as a new key detriment for risk of death. However, spatial dose patterns are typically represented as one-dimensional dose metrics of pre-defined segmented structures. Here we introduce the use of a recently developed non-parametric approach based on an extended form of optimal mass transport (OMT), called unbalanced OMT distance. Thoracic dose distributions were ranked in relation to risk of death within RTOG 0617. This agnostic approach preserves the spatial dose information without pre-selection of specific thoracic sub-regions or normalization. <h3>Materials/Methods</h3> The 409 patients with evaluable data (CTs, dose, structures and overall survival status) were retrieved from The Cancer Imaging Archive. Patients were censored at 60 months. Data was split into a 70% training and a 30% validation data (n = 286 and 123). Dose distributions were deformably registered to randomly selected reference patients using multi-step B spline. The unbalanced OMT distance measures dose spread pattern and total amount of dose differences among patients. Using a newly proposed approximation of the unbalanced OMT distance via vector-valued OMT, the highly complicated distances between pairs of dose distributions were computed efficiently. The OMT distances were translated into risk scores represented by <b>C</b>-indices: small distances (low <b>C</b>-indices) represent high-risk; large distances (high <b>C</b>-indices) represent low-risk. Risk status in the validation data was measured as distances to the training reference patients. Lastly, two sub-regions were deduced: One high-risk region based on the 50 riskiest patients (overlap of at least 80% of distributions including the highest 80% dose relative to max dose) and one low-risk region based on the 50 least risky patients. The locations of the sub-regions were qualitatively compared to those of eight deep learning auto-segmented cardio-pulmonary substructures (aorta, atria, inferior and superior vena cava (SVC), pulmonary artery (PA), ventricles). <h3>Results</h3> The highest risk of death was identified in a region overlapping with the base of the heart, including the ascending aorta, PA and the superior part of the left atrium. In contrast, the ‘safe' distributions associated with the lowest risk of death mostly avoided all cardio-pulmonary substructures with the exception of the SVC and right PA. <h3>Conclusion</h3> This non-parametric approach identified specific high-risk and low-risk regions associated with death in RTOG 0617. While there was no one-to-one correspondence between the identified high-risk region and the segmented cardio-pulmonary structures, this region focused on the base of the heart. The identified regions may direct further work on elucidating mechanisms and generalizability.

Radiomic Features of Tumor and Tumor Organismal Environment in Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiotherapy: A Retrospective Analysis of Survival Prediction

To advance towards proper concurrent chemoradiotherapy (CCRT) for locally advanced non-small cell lung cancer (LANSCLC) patients, we queried the lung CT-derived texture space to identify tumor and tumor organismal environment parameters on survival prediction.All eligible patients were included and randomly assigned into two cohorts at a ratio 5:1, with 196 in the training cohort and 40 in the independent validation cohort. Support vector machine combined with an integrated feature selection and model training approach using genetic algorithm was performed to determine the optimal set of features to predict the risk for overall survival (OS). The selected features were sorted according to their importance weights. Patients were then stratified into the high- and low-risk group based on the predicted survival status at 2 and 3 years after CCRT.A total of 92 tumor-related and lung-related features were selected as an input feature pool for the machine learning framework by the radiomics software, and 9 features were selected in the final model, including 6 tumor-related features and 3 lung-related features. Gross tumor volume, grey-level zone length matrix gray-level zone emphasis of tumor and grey level co-occurrence matrix_Energy of lung always ranked as the top three features. The areas under the curve (AUC) for 2- and 3-year OS status were 0.812 and 0.762 in the training cohort, 0.832 and 0.841 in the validation cohort, respectively. Based on imaging-derived stratification, CCRT was more successful in patients in the low-risk group than those in the high-risk group. The 2- and 3-year OS rate was 93.3% and 81.3% in the low-risk group, versus 20.0% (P = 0.0011, log-rank) and 12.5% (P = 0.0008, log-rank) in the high-risk group. When all the image features from lungs were excluded from the selected feature set, the AUCs for 2- and 3-year OS status were reduced by 0.020 and 0.019 in the training cohort, 0.035 and 0.101 in the validation cohort, respectively.Our results suggested that the image-distinct LANSCLC subpopulations had differential response to CCRT. The image-based machine learning framework proposed herein is the promising opportunity to use medical images to individualize CCRT scheme. The integrated radiomic descriptors of pulmonary tumors and lungs indicated that low-risk patients might benefit more from CCRT and consolidation immunotherapy, possibly with the support of healthier pulmonary status.

Predictors of Early Durvalumab Discontinuation After Chemoradiotherapy for Non-Small Cell Lung Cancer

Based on the PACIFIC trial, adjuvant durvalumab is now recommended after concurrent chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC), with an intended course duration of one year. In PACIFIC, approximately 50% of subjects did not complete the planned durvalumab course. Here, we explore causes and predictors of early durvalumab discontinuation to test the hypothesis that extent of normal tissue irradiation may be associated with durvalumab treatment duration.We reviewed patients treated for LA-NSCLC with definitive CRT at our institution who began adjuvant durvalumab between 2017 and 2020. Duration of durvalumab receipt and causes for early discontinuation (defined as a course duration shorter than 11.5 months) were tabulated. Cox proportional hazards models were utilized to test clinical factors (age, performance status, tumor histology, presence of known driver mutations, PD-L1 expression), measures of disease burden (stage, metabolic tumor volume [MTV] on pre-treatment FDG-PET), and treatment characteristics (mean radiotherapy doses received by the esophagus, heart, and lungs) as predictors of early durvalumab discontinuation. These variables were also tested as predictors of progression-free survival (PFS) duration after durvalumab initiation. The Kaplan-Meier method was utilized to estimate rates of durvalumab completion and PFS for the entire cohort and for patient subgroups.Fifty-three patients met inclusion criteria. Nineteen patients completed a one-year course of durvalumab, twenty-eight patients discontinued durvalumab early, and six are still receiving durvalumab. The actuarial rate of completing a one-year durvalumab course was 36%. Reasons for early durvalumab discontinuation were disease progression (n = 10), lung toxicity (n = 8), other toxicity (n = 6), and death unrelated to cancer progression or treatment toxicity (n = 4). Univariate and multivariate Cox models identified mean heart dose as the only statistically significant predictor of early immunotherapy discontinuation (HR 1.11 per Gy, 95% CI 1.01 to 1.21, P = 0.025). The rate of durvalumab completion for patients with mean heart dose below the cohort median (9.7 Gy) was 55%, compared to only 20% for patients with higher mean heart doses (log rank P = 0.020). Mean heart dose was also the only statistically significant predictor of PFS after immunotherapy initiation in a multivariable Cox model (HR 1.19 per Gy, 95% CI 1.07 to 1.32, P = 0.001). Median PFS duration for patients with mean heart dose below the cohort median was 32 months, compared to only 8 months for patients with higher mean heart doses (log rank P < 0.001).For LA-NSCLC patients treated with chemoradiotherapy followed by immunotherapy, extent of cardiac irradiation may be a risk factor for early immunotherapy discontinuation and disease recurrence or death. A multi-institutional validation study is underway.

Prognostic impact of pneumonitis after durvalumab therapy in patients with locally advanced non-small cell lung cancer

SummaryBackground. Prognostic data on Japanese patients receiving durvalumab after chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC) are insufficient. Whether pneumonitis has prognostic implications in patients with LA-NSCLC who have received durvalumab also remains unclear. Methods. We retrospectively assessed the data of 82 consecutive patients who had received durvalumab after CRT at our institution between May 2018 and August 2020. A multi-state model was used to establish the associations between co-variables and progression-free survival (PFS). Results. The median observation period for all the censored cases was 14.5 months (5.7–28.9 months), the median PFS was 22.7 months, and the 12-month PFS rate was 62.3% (95% CI: 50.2%-72.3%). The median percentage of the lung volume receiving a radiation dose in excess of 20 Gray (V20) was 22% (4%-35%). Thirteen patients (16%) had Grade 1 pneumonitis before receiving durvalumab, and 62 patients developed pneumonitis after durvalumab (Grades 1, 2, and 3 in 25 [30%], 32 [39%], and 4 [5%], respectively). Twenty-four patients (29%) completed the 1-year durvalumab treatment period, 16 patients (20%) were continuing to receive treatment, and 42 (51%) had discontinued treatment. In a multi-state analysis, patients with pneumonitis before durvalumab therapy had a poorer PFS than those without pneumonitis (HR: 4.29, p = 0.002). The development of Grade 2 or higher pneumonitis after durvalumab was not a significant prognostic factor for PFS (HR: 0.71, p = 0.852). Conclusion. Grade 2 or higher pneumonitis after durvalumab was not a prognostic factor of PFS in LA-NSCLC patients received durvalumab.

MA06.01 Death From Intercurrent Disease After Proton- Versus Photon-Based Chemoradiotherapy for Non-Small Cell Lung Cancer

Patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiotherapy (CRT) often have cardiopulmonary comorbidities and receive significant radiation dose to normal structures. One way to reduce normal tissue exposure is with proton beam therapy (PBT). We sought to determine if PBT was associated with a reduced risk of death from intercurrent disease in this patient population. We retrospectively reviewed the records of 187 patients with LA-NSCLC who received definitive CRT with either PBT (n=98) or photon therapy (n=89) between December 2008 and November 2016 at a single academic center. No patient received consolidation immunotherapy as this cohort predated the results of the PACIFIC trial. Baseline patient-, tumor-, and treatment-related parameters were collected. Primary endpoint was death from intercurrent disease (DID), defined as death in the absence of disease progression. DID was compared between PBT and photon therapy groups using the cumulative incidence function and Gray’s test and modelled using the Fine-Gray method. Disease progression was considered a competing event. Secondary endpoint was overall survival (OS), assessed using the Kaplan-Meier method and Cox regression. The PBT group was older (median 69 years vs 62 years, p<0.001), had a more extensive smoking history (median 40 pack-years vs 30 pack-years, p=0.043), and had a greater burden of pre-CRT cardiovascular events (54.1% vs 34.8%, p=0.008). Median radiotherapy dose in both groups was 66.6Gy (range, 52.2-74Gy). The PBT group experienced lower mean heart dose (MHD) (median 6.7Gy vs 15Gy, p<0.001), total lung V5Gy (median 35.9% vs 48.2%, p<0.001), contralateral mean lung dose (median 0.97Gy vs 5.9Gy, p<0.001), and mean esophageal dose (MED) (median 22.1Gy vs 26.5Gy, p=0.003). Median follow-up was 28.8 months (range, 3.6-131.6 months). Following CRT, 25 patients (13.4%) experienced DID. Presumed causes of DID included: respiratory failure due to congestive heart failure, COPD, pneumonia, or aspiration (n=10), out-of-hospital cardiopulmonary arrest of unclear etiology (n=4), undifferentiated sepsis (n=2), probable radiation pneumonitis (n=1), esophagopleural fistula (n=1), and unknown (n=7). 3-year cumulative incidence of DID was 7.1% in the PBT group versus 14.6% in the photon therapy group (p=0.098). PBT (subdistribution hazard ratio [sHR] 0.25, p=0.0042), MHD (sHR 1.06/Gy, p=0.0018), and MED (sHR 1.05/Gy, p=0.019) were associated with a reduced, increased, and increased risk of DID, respectively, after controlling for age and ECOG performance status in three separate 3-variable regression models. OS was similar between the PBT and photon therapy groups (median 29 months vs 28.8 months, p=0.6; HR 1.09, p=0.6). MHD (HR 1.02/Gy, p=0.013) was associated with worse OS after controlling for age, ECOG performance status, baseline pulmonary comorbidity, and internal gross tumor volume. Patients receiving MHD >10Gy vs ≤10Gy experienced higher 3-year cumulative incidence of DID (15.6% vs 6.7%, p=0.049) and inferior OS (median 22.9 months vs 34.1 months, p<0.001). In this cohort of patients treated with definitive CRT for LA-NSCLC, PBT was associated with reduced cardiac, pulmonary, and esophageal dose and reduced risk of DID on multivariable analysis. These results suggest PBT may have a clinically meaningful benefit in this population.

P29.02 Early GLS Changes Detection After Chemoradiation in Locally Advanced NSCLC

Chemoradiation is the standard treatment in locally advanced NSCLC (LA-NSCLC) patients and thanks to recent combination with immunotherapy, median survival has reached unexpected improvements. In this new scenario, survivorship questions have become unmet needs, preventing toxicity a clear goal of the most current research. Cardiotoxicity is linked to thoracic irradiation with clinical manifestations such as pericardial disease, ischemic heart disease, nonischemic cardiomyopathy, valvular disease, conduction abnormalities, and arrhythmias.