High-dose Thoracic Radiotherapy Research Articles

Reduced frequency and severity of radiation esophagitis without marginal failure risk by contralateral esophagus sparing IMRT in stage III non-small cell lung cancer patients undergoing definitive concurrent chemoradiotherapy

PurposeRadiation esophagitis is frequent and annoying toxicity in high dose thoracic radiation therapy. Contalateral esophagus sparing intensity modulated radiation therapy (CES-IMRT) has been proposed to mitigate this problem, and this is to report the impact of CES-IMRT in definitive concurrent chemoradiotherapy (dCCRT) for lung cancer patients. Materials and methodsFrom January 2021 till May 2023, 183 stage III non-small cell lung cancer patients underwent dCCRT. Esophagus was located within 1 cm from internal target volume in 159 patients. We comparatively evaluated the frequency and severity of esophagitis by pain-killer usage, analgesic quantification algorithm (AQA) score, and failure patterns in 159 CES-necessary patients. ResultsAll patients underwent dCCRT (66 Gy in 30 fractions with concurrent chemotherapy). Actual CES-IMRT application was determined based on the discretion of responsible radiation oncologists: CES-applied in 41 patients; and CES-unapplied in 118. CES-applied patients experienced pain events less frequently (pain-killer usage: 53.7 % vs. 77.1 %, p = 0.008) and less severely (AQA score of 2–3: 39.0 % vs. 68.6 %, p = 0.002). On multivariate analyses, overlapping volume of esophagus and planning target (HR = 1.32, 95 % CI 1.12–1.55, p = 0.001) and CES-IMRT application (HR = 0.31, 95 % CI 0.13–0.76, p = 0.010) were associated with AQA score of 2–3 less frequently. There were no differences in failure pattern, progression-free survival, and overall survival. ConclusionsCES-IMRT application resulted in less frequent and less severe pain events without compromising oncologic outcomes. Further studies, preferably in a randomized fashion, would be desired.

Prognostic nomogram for overall survival in patients with stage IV non-small cell lung cancer treated with chemotherapy combined with high-dose thoracic radiotherapy.

e20607 Background: Although the targeted therapy and immunotherapy have become the first line options for selected stage IV non-small cell lung cancer (NSCLC) patients. However, there are instances where certain patients are not administered targeted therapy or immunotherapy due to a variety of factors, chemotherapy and radiotherapy remain the main way to treat such patients. This study aimed to construct a prognostic nomogram for patients with stage IV NSCLC treated with chemotherapy combined with high-dose (≥ 60 Gy) thoracic radiotherapy. Methods: The nomogram was based on a retrospective study of 335 patients with stage IV NSCLC who treated with chemotherapy combined with high-dose (≥ 60 Gy) thoracic radiotherapy were hospitalized between January 2010 and January 2018(patient did not receive TKI therapy or immunotherapy). The patients were randomly assigned to either a primary cohort (n = 234) or a validation cohort (n = 101) at a ratio of 7 : 3. In the primary cohort, a univariate analysis of the clinical or therapeutic factors that may predict OS was performed using a Cox regression model, with P < 0.05 indicating statistical significance. The variables from the univariate analysis that affected OS significantly were included in the Cox regression model for the multivariate analysis. A nomogram was then created based on the results of multivariate analysis and using the “rms,” “foreign,” and “survival” R version 4.0.3 software packages. The discriminatory ability of the nomogram was measured using the area under the curve (AUC) of a receiver operating curve (ROC). Results: Multivariate logistic regression analysis revealed that malignant pericardial effusion, adrenal metastasis, elevated lactate dehydrogenase levels, and excessive planning target volume were independent risk factors for poorer 1–3 year overall survival (OS), while a higher radiotherapy dose for the primary lesion was associated with better OS. Nomogram prediction models were constructed using these five variables. The AUC of the ROC for 1-year, 2-year, and 3-year OS in the primary cohort were 0.685, 0.729, and 0.816, respectively. In the validation cohort, the AUC of the ROC for 1-year, 2-year, and 3-year OS were 0.706, 0.749, and 0.797, respectively. The Kaplan-Meier survival analysis showed that differentiation between the high-risk group and low-risk group using the prediction model had a direct, significant effect on survival in both the primary cohort ( P < 0.001) and validation cohort ( P = 0.004). Conclusions: The nomogram model constructed in this study may be used to objectively predict the prognosis and OS of patients with stage IV NSCLC treated with chemotherapy and high-dose thoracic radiotherapy. Identify patients who may not benefit from high-dose thoracic radiotherapy prior to treatment to avoid overtreatment.

Alleviating lung injury and pulmonary fibrosis in radiotherapy-immunotherapy combination: The role of low-dose radiation therapy.

e14632 Background: Lung cancer continues to be the primary cause of cancer-related mortality on a global scale. The integration of radiotherapy and immunotherapy has yielded significant advancements in the treatment of locally advanced non-small cell lung cancer. However, the occurrence of treatment-associated pneumonia remains the predominant adverse event necessitating treatment cessation and permanent medication discontinuation. The immune-modulating effects of radiation therapy on the body contribute to a complex interplay between radiation and inflammation. Low-dose radiotherapy (LD-RT) has historically been utilized for the management of benign inflammatory conditions. Recently, LD-RT was found to be effective in treating severe pneumonia in patients with severe COVID-19 as well as acute respiratory distress syndrome (ARDS). This investigation seeks to examine the impact of LD-RT on lung tissue morphology and the inflammatory immune microenvironment in preclinical models of lung injury induced by high-dose radiotherapy combined with programmed death-1(PD-1) inhibitor therapy. Methods: 6-8 week old C57BL/6 mice were treated with a single high-dose thoracic radiotherapy (15Gy) and the PD-1 inhibitor (once a week), with or without the low-dose radiotherapy (1.0/1.5Gy) four weeks later. Lung tissue was collected one and a half months and three months respectively after the initial high-dose radiotherapy for evaluation using HE and Masson staining, Image J software for analysis of collagen volume fraction (CVF), and immunohistochemical staining for CD3+ and CD8+ T lymphocytes. Cytokine transforming growth factor (TGF)-β1、interleukin (IL)-6 and tumor necrosis factor (TNF)-α level in lung tissue was detected by ELISA. Statistical analysis was performed using GraphPad Prism 9.5.0 software. Results: The radiotherapy-immunotherapy combination (iRT) group exhibits notable lung injury characterized by the proliferation of alveolar type II epithelial cells, thickening of alveolar septa, interstitial edema, pulmonary congestion and bleeding, increased infiltration of inflammatory cells, and significant deposition of interstitial collagen fibers. In contrast, the iRT+ LD-RT group demonstrates a significant decrease in lung tissue damage, interstitial fibrosis, collagen volume fraction (CVF), levels of IL-6 and TGF-β, as well as the infiltration of CD3+ and CD8+T cells compared to the iRT group. Conclusions: Low-dose radiation has the potential to ameliorate lung injury induced by the combination of radiotherapy and PD-1 inhibitors by modulating the inflammatory milieu, thereby potentially mitigating the development of pulmonary fibrosis.

Major Cardiovascular Events after Chemoradiotherapy with or without Durvalumab in Patients with Stage III Non-Small Cell Lung Cancer: Supplementary Analysis

RTOG 0617 showed that cardiac events are relatively common after high-dose thoracic radiotherapy. The aim of this study was to investigate the incidence and risk of major cardiovascular events (MACE) after concurrent chemoradiotherapy (CCRT) with or without durvalumab in patients with stage III non-small cell lung cancer (NSCLC) using the data from a multi-institutional study in Japan. Patients who received CCRT for stage III NSCLC between July 2018 and July 2019 were enrolled in a multi-institutional study in Japan. MACE was defined as follows: symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure. The cumulative incidence of MACE, accounting for death as a competing risk, was calculated. Pre-existing coronary heart disease (CHD) included coronary artery disease, congestive heart failure, peripheral vascular disease, stroke, and extensive coronary artery calcification. The association between patient/treatment-related factors and MACE was assessed by multivariate analysis. Among 178 patients with a median follow-up period of 42.5 months, 13 patients developed MACEs. The 3-year cumulative incidence of MACE was 6.9% (95% confidence interval [CI], 4.0-11.9%). Univariate analysis showed that female sex and mean heart dose (MHD) were marginally associated (3-year cumulative incidence, male 5.6% vs. female 12.1%; P = 0.12; MHD ≥ 6.3 Gy 4.8% vs. < 6.3 Gy 9.1%; P = 0.13), and pre-existing CHD was significantly associated with an increased risk of MACE (no CHD 4.3% vs. CHD 16.8%; P = 0.026). Consolidation durvalumab was not associated with an increased risk of MACE (no durvalumab 5.2% vs. durvalumab 7.4%; P = 0.89). Multivariate analysis showed that pre-existing CHD was significantly associated with MACE (hazard ratio, 4.22; 95% CI, 1.30-13.7; P = 0.016). The incidence of MACE based on the real-world data in Japan was lower than previously reported. Pre-existing CHD was associated with an increased risk of MACE after CCRT in patients with stage III NSCLC, whereas the administration of consolidation durvalumab was not associated with an increased risk of MACE.

New Insights into the Understanding of Mechanisms of Radiation-Induced Heart Disease.

Cancer patients who receive high-dose thoracic radiotherapy may develop radiation-induced heart disease (RIHD). The clinical presentation of RIHD comprises coronary artery atherosclerosis, valvular disease, pericarditis, cardiomyopathy, and conduction defects. These complications have significantly reduced due to the improved radiotherapy techniques. However, such methods still could not avoid heart radiation exposure. Furthermore, people who received relatively low-dose radiation exposures have exhibited significantly elevated RIHD risks in cohort studies of atomic bomb survivors and occupational exposures. The increased potential in exposure to natural and artificial ionizing radiation sources has emphasized the necessity to understand the development of RIHD. The pathological processes of RIHD include endothelial dysfunction, inflammation, fibrosis, and hypertrophy. The underlying mechanisms may involve the changes in oxidative stress, DNA damage response, telomere erosion, mitochondrial dysfunction, epigenetic regulation, circulation factors, protein post-translational modification, and metabolites. This review will discuss the recent advances in the mechanisms of RIHD at cellular and molecular levels.

Consolidative high-dose thoracic radiotherapy for limited metastatic nonsmall cell lung cancer: Focusing on oligo-progressive disease.

Prior clinical data have shown a significant survival benefit of consolidative local radiotherapy for patients with limited metastatic non-small cell lung cancer (NSCLC). Therefore, this study aimed to evaluate the impact of consolidative high-dose thoracic radiotherapy on local control rates and survivals in patients with limited metastatic NSCLC, especially focusing on oligo-progressive disease. We retrospectively reviewed the medical records of 45 patients with limited metastatic NSCLC who received consolidative high-dose thoracic radiotherapy at the Korea University Guro Hospital between March 2015 and December 2020. In the current study, we included patients who showed partial response, stable disease, or oligo-progressive disease on tumor response evaluation after systemic treatment. All patients underwent stereotactic body radiation therapy (23 patients) or intensity-modulated radiation therapy (IMRT, 22 patients). The median follow-up time was 42 months (range: 5-88 months). The overall 2-year disease-free survival (DFS) and overall survival (OS) rates were 80.7% and 88.4%, respectively. Among the 45 patients, only two patients treated with IMRT showed in-field local recurrence. There was no local failure among the patients who showed oligo-progressive disease after systemic treatment. In addition, the response to systemic treatment was not a significant factor for either DFS or OS rates (p=.471 and p=.414, respectively) in univariate analysis. Consolidative high-dose thoracic radiotherapy improves local control rates and helps achieve long-term survival in patients with limited metastatic NSCLC. It is also effective and should be considered in patients with oligo-progressive disease after systemic treatment.

ES11.02 Advances in Thoracic Radiation in SCLC

ES11.02 Advances in Thoracic Radiation in SCLC

1665TiP High-dose vs standard-dose thoracic radiotherapy for extensive stage small cell lung cancer: Study protocol for a phase III randomized trial

The optimal thoracic radiation dose for patients with extensive stage small cell lung cancer (ES-SCLC) who respond to chemotherapy remains unclear. This study aims to determine whether high-dose thoracic radiotherapy has superior efficacy compared with standard-dose thoracic radiotherapy in ES-SCLC patients.

High-dose thoracic radiation therapy for non-small cell lung cancer: a novel grading scale of radiation-induced lung injury for symptomatic radiation pneumonitis

BackgroundSymptomatic radiation pneumonitis (RP) may be a serious complication after thoracic radiation therapy (RT) for non-small cell lung cancer (NSCLC). This prospective observational study sought to evaluate the utility of a novel radiation-induced lung injury (RILI) grading scale (RGS) for the prediction of RP.Materials and methodsData of 41 patients with NSCLC treated with thoracic RT of 60–66 Gy were analysed. CT scans were scheduled before RT, one month post-RT, and every three months thereafter for one year. Symptomatic RP was defined as Common Terminology Criteria for Adverse Events grade ≥ 2. RGS grading ranged from 0 to 3. The inter-observer variability of the RGS was assessed by four senior radiologists. CT scans performed 28 ± 10 days after RT were used to analyse the predictive value of the RGS. The change in the RGS severity was correlated to dosimetric parameters.ResultsThe CT obtained one month post-RT showed RILI in 36 (88%) of patients (RGS grade 0 [5 patients], 1 [25 patients], 2 [6 patients], and 3 [5 patients]). The inter-observer agreement of the RGS grading was high (Kendall’s W coefficient of concordance = 0.80, p < 0.01). Patients with RGS grades 2–3 had a significantly higher risk for development of RP (relative risk (RR): 2.4, 95% CI 1.6–3.7, p < 0.01) and RP symptoms within 8 weeks after RT (RR: 4.8, 95% CI 1.3–17.6, p < 0.01) compared to RGS grades 0–1. The specificity and sensitivity of the RGS grades 2–3 in predicting symptomatic RP was 100% (95% CI 80.5–100%) and 45.4% (95% CI 24.4–67.8%), respectively. Increase in RGS severity correlated to mean lung dose and the percentage of the total lung volume receiving 5 Gy.ConclusionsThe RGS is a simple radiologic tool associated with symptomatic RP. A validation study is warranted.

Phase 3 comparison of high-dose once-daily (QD) thoracic radiotherapy (TRT) with standard twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC): CALGB 30610 (Alliance)/RTOG 0538.

8505 Background: Although level 1 evidence is lacking, the majority of patients (pts) with LSCLC are treated with a high dose QD TRT regimen in clinical practice. CALGB 30610/RTOG 0538 was designed to determine if administering high dose TRT would improve overall survival (OS), compared with standard 45 Gy BID TRT, in LSCLC pts treated with chemoradiotherapy. Methods: Eligible pts had LSCLC, ECOG performance status (PS) 0-2 and regional lymph node involvement excluding contralateral hilar or supraclavicular nodes. This phase 3 trial was conducted in 2 stages. In the first stage, pts were randomized 1:1:1 to 45 Gy BID over 3 weeks, 70 Gy QD over 7 weeks, or 61.2 Gy concomitant boost (CB) over 5 weeks. For the second stage, the study planned discontinuation of one high dose arm based on interim toxicity analysis with patients then randomized 1:1 in the two remaining arms. TRT was given starting with either the 1st or 2nd (of 4 total) chemotherapy cycles. The primary endpoint was OS measured from date of randomization. Results: The trial opened 03/15/2008 and closed 12/01/2019 upon completing accrual, with the CB arm discontinued 3/11/2013 after interim analysis. This analysis includes 638 pts randomized to 45 Gy BID TRT (n = 313) or 70 Gy QD TRT (n = 325). Median age was 63 years (range 37-81), the majority of pts were Caucasian (86%), female (52%), and with ECOG PS 0-1 (95%). After median follow-up of 2.84 years (IQR:1.35 -5.61) for surviving pts, QD compared to BID did not result in a significant difference in OS (HR 0.94, 95% CI: 0.76-1.2, p = 0.9). Median, 2- and 4-year OS for QD were 30.5 months (95% CI: 24.4-39.6), 56% (95% CI: 0.51-0.62), and 39% (95% CI: 0.33-0.45), and for BID 28.7 months (95% CI: 26.2-35.5), 59% (95% CI: 0.53-0.65), and 35% (95% CI: 0.29-0.42). QD also did not result in a significant difference in PFS (HR 0.96, 95% CI: 0.78-1.18, p = 0.94). Most grade 3+ hematologic and non-hematologic adverse events (AEs) were similar between cohorts. Rates of grade 3+ febrile neutropenia, dyspnea, esophageal pain and dysphagia for QD were 12.6%,7%, 11.6% and 11.3%, and for BID 13.6%, 4%, 11.2 % and 9.5%. Grade 5 AEs were reported in 3.7% and 1.7% of the QD and BID cohorts, respectively. Results will be updated at presentation. Conclusions: High dose QD TRT to 70 Gy did not significantly improve OS compared with standard 45 Gy BID TRT. Nevertheless, favorable outcomes on the QD arm provide the most robust evidence available supporting high dose once-daily TRT as an acceptable option in LSCLC. Outcomes from this study, the largest conducted in LSCLC to date, will help guide TRT decisions for this patient population. Support: U10CA180821, U10CA180882; Clinical trial information: NCT00632853.

Short Communication: Interim toxicity analysis for patients with limited stage small cell lung cancer (LSCLC) treated on CALGB 30610 (Alliance) / RTOG 0538

IntroductionThe CALGB 30610/RTOG 0538 randomized trial was designed to test whether high-dose thoracic radiotherapy (TRT) would improve survival compared with 45 Gy twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC). Two piloted experimental TRT regimens were of interest to study, 70 Gy daily (QD) and 61.2 Gy concomitant boost (CB). Driven by concerns about adequate patient accrual, a study design was employed that eliminated one experimental TRT arm based on early interim toxicity and tolerability, with the study then continuing as a traditional 2-arm phase III study. MethodsPatients with LSCLC were assigned to receive four cycles of cisplatin and etoposide chemotherapy with one of 3 TRT regimens starting with either the first or second cycle of chemotherapy. The interim endpoint was the cumulative highest toxicity calculated from a scoring system based on treatment-related grade 3 and higher toxicity and the ability to complete therapy in the experimental arms. ResultsThe final interim analysis was performed after 70 patients accrued to each experimental cohort, and a difference in treatment related toxicity scoring was not found (p = 0.739). Severe esophageal toxicity was comparable in both cohorts. Pulmonary toxicity was low overall, though 4 patients (5.7 %) on the 61.2 Gy arm developed grade 4 dyspnea, which was not observed in the 70 Gy arm. A protocol mandated decision was made to discontinue the 61.2 Gy arm following review of toxicity with the Data and Safety Monitoring Board. ConclusionA randomized trial design using a planned early interim toxicity analysis to discriminate between experimental treatment arms is feasible in a phase III setting. Refinement of the design could increase the likelihood of detecting clinically meaningful differences in toxicity in future studies.

Sequential Treatment with an Immune Checkpoint Inhibitor Followed by a Small-Molecule Targeted Agent Increases Drug-Induced Pneumonitis.

PurposeImmune checkpoint inhibitors (ICI) and targeted small-molecule drugs are mainstay elements of lung cancer chemotherapy. However, they are associated with development of pneumonitis, a rare, but potentially life-threatening event. We analyzed lung cancer patients treated with ICI to evaluate the effect of sequential therapeutic administration on the incidence of pneumonitis.Materials and MethodsIn this retrospective study, 242 patients were included. Serial radiologic findings taken during and immediately after ICI treatment were reviewed. Factors that increased pneumonitis and the relationship between peri-ICI chemotherapy and the development of pneumonitis were evaluated.ResultsPneumonitis developed in 23 patients (9.5%); severe pneumonitis (grade ≥ 3) occurred in 13 of 23 patients (56%); pneumonitis-related death occurred in six. High-dose thoracic radiation (≥ 6,000 cGy) revealed a tendency toward high risk of pneumonitis (odds ratio, 2.642; 95% confidence interval, 0.932 to 7.490; p=0.068). Among 149 patients followed for ≥ 8 weeks after the final ICI dose, more patients who received targeted agents within 8-weeks post-ICI experienced pneumonitis (3/16, 18.8%) compared with patients who received cytotoxic agents (4/54, 7.4%) or no chemotherapy (4/79, 5.1%) (p=0.162). Targeted therapy was associated with earlier-onset pneumonitis than treatment with cytotoxic agents (35 vs. 62 days post-ICI, p=0.007); the resulting pneumonitis was more severe (grade ≥ 3, 100% vs. 0%, p=0.031).ConclusionSequential administration of small-molecule targeted agents immediately after ICI may increase the risk of severe pneumonitis. The sequence of chemotherapy regimens that include ICI and targeted agents should be carefully planned to reduce the risk of pneumonitis in lung cancer patients.

The utilization patterns and comparative effectiveness of systemic therapy with high-dose thoracic radiotherapy or low-dose thoracic radiotherapy versus systemic therapy alone in newly diagnosed metastatic non-small cell lung cancer patients

We used the National Cancer Database (NCDB) to investigate the utilization and effectiveness of high-dose thoracic radiotherapy (RT) with systemic therapy (ST), compared to low-dose RT with ST, or ST alone in patients with metastatic non-small cell lung cancer (mNSCLC), hypothesizing that the use of high-dose thoracic RT with ST would increase in time and be associated with improved overall survival (OS). We identified mNSCLC patients diagnosed between 2004 and 2014 whose initial treatment comprised ST and thoracic RT (ST-RT; n = 46,315) or ST and no thoracic or extrathoracic RT (ST-only; n = 113,009). RT dose was grouped by biologically effective dose (BED10). OS was compared using multivariable regression models and propensity score (PS)–matched analyses. Median follow-up was 9.1 months and 25.8 months among those alive at last follow-up. Among ST-RT patients, 16.9% and 2.3% received BED10 70–99 Gy (n = 7806) and BED10 ≥ 100 Gy (n = 1049), respectively. Compared to the ST-only group, ST-RT patients receiving a BED10 of 40–69 Gy (HR 0.95, p < 0.001), 70–99 Gy (HR 0.69, p < 0.001), or ≥ 100 Gy (HR 0.68, p < 0.001) had improved OS on multivariable analysis, while patients receiving a BED10 of < 40 Gy (HR 1.40, p < 0.001) did not. Patients who received high-dose RT (BED10 ≥ 70 Gy; HD-RT) had improved OS compared to PS-matched controls in the ST-only group (HR 0.68, p < 0.001). Utilization of HD-RT increased year-by-year over the study period. HD-RT utilization increased and was associated with improved OS versus ST alone or ST with low-dose RT. These findings are consistent with results from recently published randomized phase II studies.

Higher thoracic radiation dose is beneficial in patients with extensive small cell lung cancer.

PurposeThe effectiveness of thoracic radiation therapy (TRT) in extensive-stage small cell lung cancer (ES-SCLC) patients is increasingly reported, but there is no definite consensus on its application. The aim of this study was to identify factors associated with better outcomes of TRT among patients with ES-SCLC, focusing on whether a higher TRT dose could improve treatment outcome.Materials and MethodsThe medical records of 85 patients with ES-SCLC who received TRT between January 2008 and June 2017 were retrospectively reviewed. Eligibility criteria were a biological effective dose with α/β = 10 (BED) higher than 30 Gy10 and completion of planned radiotherapy.ResultsDuring a median follow-up of 5.3 months, 68 patients (80.0%) experienced disease progression. In univariate analysis, a BED >50 Gy10 was a significant prognostic factor for overall survival (OS; 40.8% vs. 12.5%, p = 0.006), progression-free survival (PFS; 15.9% vs. 9.6%, p = 0.004), and intrathoracic PFS (IT-PFS; 39.3% vs. 20.5%, p = 0.004) at 1 year. In multivariate analysis, a BED >50 Gy10 remained a significant prognostic factor for OS (hazard ratio [HR] = 0.502; 95% confidence interval [CI], 0.287–0.876; p = 0.015), PFS (HR = 0.453; 95% CI, 0.265–0.773; p = 0.004), and IT-PFS (HR = 0.331; 95% CI, 0.171–0.641; p = 0.001). Response to the last chemotherapy was also associated with better OS in both univariate and multivariate analysis.ConclusionA TRT dose of BED >50 Gy10 may be beneficial for patients with ES-SCLC. Further studies are needed to select patients who will most benefit from high-dose TRT.

Abstract 4863: Discovery of novel metabolomic plasma biomarkers predictive of radiation induced cardiac toxicity

Abstract Introduction: Although advancements in cancer treatment have led to increased survivorship, radiation induced heart disease (RIHD) remains a major source of acute and long term morbidity and mortality for cancer survivors, for which there are no diagnostic tests in routine clinical use due to lack efficacy or excessive cost. Several studies have documented RIHD; however, none of these investigations have examined the utility of using metabolomics to prospectively identify cancer survivors who are at risk of cardiotoxicity. The overarching goal of this pilot study is to determine whether biomolecules secreted in the circulation by latent yet developing cardiotoxic processes can be leveraged for predicting risk of cardiac dysfunction in cancer survivors. Approach: We used metabolomics/lipidomics analysis, an emerging field that provides information on biological perturbations based on relative changes in the plasma levels of endogenous metabolites, for a retrospective outcome analysis study. Patients treated at GUH with radiation therapy (RT) for locally advanced esophageal cancer (n = 11 x 3 time points), who underwent serial cardiac MRI’s were selected. We identified a subset of patients who developed radiation related heart ischemia and fibrosis in the inferior/ basal segment of the heart associated with the high dose region, as well as associated cardiac functional impairments (n = 6 x 3 time points). We also analyzed plasma and cardiac tissue samples from groups male Sprague Dawley (SD) rats that were either sham irradiated or received fractionated doses (9 Gy per day x 5 days) of targeted X-ray radiation to the heart. Metabolomic analysis was used as a correlative approach for delineation of novel biomarkers associated with radiation induced cardiac toxicity. Results: Global metabolomics and lipidomics analyses have yielded important data for developing classification algorithms with high predictive accuracy. We are in the process of performing statistical analyses to determine the sensitivity and specificity of the resultant panel, and any influence provided by age and gender on the predictive performance of the biomarker panel. These data will be presented at the AACR meeting. Conclusion: Cardiac dysfunction following cancer therapy leads to significant morbidity and mortality. While our cohort includes esophageal cancer patients, we believe the cardiac toxicities detailed previously are applicable to other patient populations receiving high dose thoracic radiation therapy. We believe findings from this study are of significant interest to the scientific community since there are critical gaps in knowledge related to mechanisms of cardiac injury, clinical prediction, screening, prevention, and treatment. Supported by Cancer Center Support Grant (CCSG/NCI/NIH) and funding Ruesch Foundation Citation Format: Keith Unger, Michael Girgis, Meena Rajagopal, Yeline Ceh, Meth Jayatilake, Yaoxiang Li, Amrita K. Cheema. Discovery of novel metabolomic plasma biomarkers predictive of radiation induced cardiac toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4863.

Prognostic factors in patients with stage IV small cell lung cancer: A nomogram prediction model based on different doses of thoracic radiotherapy

Objective To evaluate the effect of different doses of thoracic radiotherapy (TRT) upon the clinical prognosis of patients with extensive-stage (stage Ⅳ) small cell lung cancer (ES-SCLC) and establish a Nomogram prediction model. Methods Clinical data of 144 patients pathologically diagnosed with ES-SCLC undergoing TRT in Tianjin Medical University Cancer Hospital from month, 2010 to month, 2016 were retrospectively analyzed. Clinical characteristics, treatment data and responses were evaluated. A Nomogram was established by using Cox’s proportional hazard regression model to predict the overall survival (OS). The prediction capability and accuracy were assessed by the concordance index (C-index) and a calibration curve between the model and verification groups. Results The median follow-up time was 31.9 months. The 2-year OS rate was 20.3%.The Nomogram model demonstrated that TRT dose, liver metastases, oligometastases/polymetastases, number of chemotherapy cycle and response to chemotherapy were significantly correlated with clinical prognosis. The calibration curve revealed that the predicted and actual OS were highly consistent. The C-index was calculated as 0.701.In the subgroup analyses, patients with high-dose TRT obtained significantly better OS than their counterparts with low-dose TRT. Conclusion The Nomogram prediction model based on different TRT doses can accurately predict the OS rate of ES-SCLC patients, which is an individualized model for predicting the survival probability. Key words: Lung neoplasms/chemotherapy; Lung neoplasms/radiotherapy; Prognosis

Toxicity Related to Radiotherapy Dose and Targeting Strategy: A Pooled Analysis of Cooperative Group Trials of Combined Modality Therapy for Locally Advanced Non–Small Cell Lung Cancer

ObjectiveConcurrent chemoradiotherapy (CRT) was the standard treatment for locally advanced NSCLC (LA-NSCLC). This study was performed to examine thoracic radiotherapy (TRT) parameters and their impact on adverse events (AEs). MethodsWe collected individual patient data from 3600 patients with LA-NSCLC who participated in 16 cooperative group trials of concurrent CRT. The TRT parameters examined included field design strategy (elective nodal irradiation [ENI] versus involved-field [IF] TRT [IF-TRT]) and TRT dose (60 Gy versus ≥60 Gy). The primary end point of this analysis was the occurrence of AEs. ORs for AEs were calculated with univariable and multivariable logistic models. ResultsTRT doses ranged from 60 to 74 Gy. ENI was not associated with more grade 3 or higher AEs than IF-TRT was (multivariable OR = 0.77, 95% confidence interval [CI]: 0.543–1.102, p = 0.1545). Doses higher than 60 Gy (high-dose TRT) were associated with significantly more grade 3 or higher AEs (multivariable OR = 1.82, 95% CI: 1.501–2.203, p < 0.0001). In contrast, ENI was associated with significantly more grade 4 or higher AEs (multivariable OR = 1.33, 95% CI: 1.035–1.709, p = 0.0258). Doses higher than 60 Gy were also associated with more grade 4 or higher AEs (multivariate OR = 1.42, 95% CI: 1.191–1.700, p = 0.0001). Grade 5 AEs plus treatment-related deaths were more frequent with higher-dose TRT (p = 0.0012) but not ENI (p = 0.099). ConclusionsFor patients with LA-NSCLC treated with concurrent CRT, IF-TRT was not associated with the overall risk of grade 3 or higher AEs but was associated with significantly fewer grade 4 or higher AEs than ENI TRT. This is likely the result of irradiation of a lesser amount of adjacent critical normal tissue. Higher TRT doses were associated significantly with grade 3 or higher and grade 4 or higher AEs. On the basis of these findings and our prior report on survival, CRT using IF-TRT and 60 Gy (conventionally fractionated) were associated with more favorable patient survival and less toxicity than was the use of ENI or higher radiotherapy doses.

Receipt of thoracic radiation therapy and radiotherapy dose are correlated with outcomes in a retrospective study of three hundred and six patients with extensive stage small-cell lung cancer

BackgroundThe importance of the thoracic radiation therapy (TRT) dose has not been clearly defined in extensive stage small-cell lung cancer (ES-SCLC) and it is unclear whether improved TRT dose translates into a survival benefit. Methods306 patients with ES-SCLC were retrospectively reviewed, of which 170 received IMRT/CRT fractionation RT after ChT, and 136 received chemotherapy (ChT) alone. We adopted the time-adjusted BED (tBED) for effective dose fractionation calculation. Due to the nonrandomized nature of this study, we compared the ChT+RT with ChT groups that matched on possible confounding variables. ResultsPatients achieved 2-year OS, PFS and LC rates of 19.7%, 10.7% and 28.4%, respectively. After propensity score matching, (113 cases for each group), the rates of OS, PFS and LC at 2 years were 21.4%, 7.7% and 34.5% for ChT+TRT, and 10.3% (p<0.001), 4.6% (p<0.001) and 6.3% for ChT only (p<0.001), respectively. Among propensity score matching patients, 56 cases for each group received the high dose (tBED>50 Gy) TRT and received low dose (tBED≤50 Gy) TRT. Two-year OS, PFS and LC rates were 32.3%, 15.3% and 47.1% for the high dose compared with 17.0% (p<0.001), 12.9% (p=0.097) and 34.7% (p=0.029) for low dose radiotherapy. ConclusionsTRT added to ChT improved ES-SCLC patient OS. High dose TRT improved OS over lower doses. Our results suggest that high-dose thoracic radiation therapy may be a reasonable consideration in select patients with ES-SCLC.

High-Dose Thoracic Radiation Therapy Is Associated With Improved Survival in Metastatic Non-Small Cell Lung Cancer (NSCLC)

High-Dose Thoracic Radiation Therapy Is Associated With Improved Survival in Metastatic Non-Small Cell Lung Cancer (NSCLC)

421PD Prospective monitoring of lung function tests with CO and NO diffusion during high dose thoracic radiotherapy for lung cancer: The CONORT study

421PD Prospective monitoring of lung function tests with CO and NO diffusion during high dose thoracic radiotherapy for lung cancer: The CONORT study