High-dose Thoracic Radiotherapy Research Articles

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

Comparative Effectiveness of Aggressive Locoregional Therapy in Metastatic Lung Cancer: Associations Between High-Dose Thoracic Radiation Therapy and/or Chemoradiation Therapy and Survival in a Large Population-Based Cohort

Comparative Effectiveness of Aggressive Locoregional Therapy in Metastatic Lung Cancer: Associations Between High-Dose Thoracic Radiation Therapy and/or Chemoradiation Therapy and Survival in a Large Population-Based Cohort

High-dose, conventionally fractionated thoracic reirradiation for lung tumors

BackgroundLoco-regional recurrences and second primary lung tumors are not uncommon after high-dose thoracic radiotherapy. The availability of improved radiotherapy techniques increases options for reirradiation. We describe a single-institutional experience with high-dose conventional thoracic reirradiation for both loco-regional recurrences and new primary tumors. MethodsRetrospective chart review of patients undergoing reirradiation between February 2004 and February 2013. ResultsOf 24 patients identified, 54% had a loco-regional recurrence, and 46% a new primary tumor. The majority (63%) had stage III NSCLC at both initial and second treatment; median interval between treatments was 51 months (5–189), median follow-up after reirradiation was 19.3 months (95% CI: 2.8–35.9). Median overall survival (OS) after reirradiation was 13.5 months, with 1-year survival 51%. Median event-free survival (EFS) was 8.4 months. Median time between reirradiation and local progression (n=8) or distant progression (n=8) was 6.7 and 11.8 months, respectively. Three patients died with possible grade 5 bleeding. Other toxicities were uncommon. Planning target volume (PTV) at reirradiation was the most important prognostic factor; PTV <300 versus ≥300cc was significantly associated with median OS (17.4 vs 8.2 months, p=0.03) and EFS (14.1 vs 5.5 months, p=0.03). Magnitude of overlap between the initial and subsequent PTVs, and between dose distributions, did not influence survival. ConclusionThoracic reirradiation with high dose conventional radiotherapy appears to deliver a meaningful survival benefit in low volume new primary or recurrent lung cancer. Further studies are needed to confirm these findings, and to establish reliable normal tissue tolerance doses for reirradiation.

Radiation-Induced Lung Injury Is Mitigated by Blockade of Gastrin-Releasing Peptide

Gastrin-releasing peptide (GRP), secreted by pulmonary neuroendocrine cells, mediates oxidant-induced lung injury in animal models. Considering that GRP blockade abrogates pulmonary inflammation and fibrosis in hyperoxic baboons, we hypothesized that ionizing radiation triggers GRP secretion, contributing to inflammatory and fibrotic phases of radiation-induced lung injury (RiLI). Using C57BL/6 mouse model of pulmonary fibrosis developing ≥20 weeks after high-dose thoracic radiation (15 Gy), we injected small molecule 77427 i.p. approximately 1 hour after radiation then twice weekly for up to 20 weeks. Sham controls were anesthetized and placed in the irradiator without radiation. Lung paraffin sections were immunostained and quantitative image analyses performed. Mice exposed to radiation plus PBS had increased interstitial CD68(+) macrophages 4 weeks after radiation and pulmonary neuroendocrine cells hyperplasia 6 weeks after radiation. Ten weeks later radiation plus PBS controls had significantly increased pSmad2/3(+) nuclei/cm(2). GRP blockade with 77427 treatment diminished CD68(+), GRP(+), and pSmad2/3(+) cells. Finally, interstitial fibrosis was evident 20 weeks after radiation by immunostaining for α-smooth muscle actin and collagen deposition. Treatment with 77427 abrogated interstitial α-smooth muscle actin and collagen. Sham mice given 77427 did not differ significantly from PBS controls. Our data are the first to show that GRP blockade decreases inflammatory and fibrotic responses to radiation in mice. GRP blockade is a novel radiation fibrosis mitigating agent that could be clinically useful in humans exposed to radiation therapeutically or unintentionally.