Dataset Information

MiRNA-Related Genetic Variations Associated with Radiotherapy-Induced Toxicities in Patients with Locally Advanced Non-Small Cell Lung Cancer.

ABSTRACT: Severe radiation-induced toxicities limit treatment efficacy and compromise outcomes of lung cancer. We aimed to identify microRNA-related genetic variations as biomarkers for the prediction of radiotherapy-induced acute toxicities. We genotyped 233 SNPs (161 in microRNA binding site and 72 in processing gene) and analyzed their associations with pneumonitis and esophagitis in 167 stage III NSCLC patients received definitive radiation therapy. Sixteen and 11 SNPs were associated with esophagitis and pneumonitis, respectively. After multiple comparison correction, RPS6KB2:rs10274, SMO:rs1061280, SMO:rs1061285 remained significantly associated with esophagitis, while processing gene DGCR8:rs720014, DGCR8:rs3757, DGCR8:rs1633445 remained significantly associated with pneumonitis. Patients with the AA genotype of RPS6KB2:rs10274 had an 81% reduced risk of developing esophagitis (OR: 0.19, 95% CI: 0.07-0.51, p = 0.001, q = 0.06). Patients with the AG+GG genotype of SMO:rs1061280 had an 81% reduced risk of developing esophagitis (OR: 0.19, 95% CI: 0.07-0.53, p = 0.001, q = 0.06). Patients with the GG+GA genotype of DGCR8:rs720014 had a 3.54-fold increased risk of pneumonitis (OR: 3.54, 95% CI: 1.65-7.61, p <0.05, q <0.1). Significantly cumulative effects of the top SNPs were observed for both toxicities (P-trend <0.001). Using bioinformatics tools, we found that the genotype of rs10274 was associated with altered expression of the RPS6KB2 gene. Gene-based analysis showed DGCR8 (p = 0.010) and GEMIN4 (p = 0.039) were the top genes associated with the risk of developing pneumonitis. Our results provide strong evidence that microRNA-related genetic variations contribute to the development of radiotherapy-induced acute esophagitis and pneumonitis and could thus serve as biomarkers to help accurately predict radiotherapy-induced toxicity in NSCLC patients.

SUBMITTER: Li R

PROVIDER: S-EPMC4798772 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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MiRNA-Related Genetic Variations Associated with Radiotherapy-Induced Toxicities in Patients with Locally Advanced Non-Small Cell Lung Cancer.

Li Rong R Pu Xia X Chang Joe Y JY Ye Yuanqing Y Komaki Ritsuko R Minna John D JD Roth Jack A JA Han Baohui B Wu Xifeng X

PloS one 20160318 3

Severe radiation-induced toxicities limit treatment efficacy and compromise outcomes of lung cancer. We aimed to identify microRNA-related genetic variations as biomarkers for the prediction of radiotherapy-induced acute toxicities. We genotyped 233 SNPs (161 in microRNA binding site and 72 in processing gene) and analyzed their associations with pneumonitis and esophagitis in 167 stage III NSCLC patients received definitive radiation therapy. Sixteen and 11 SNPs were associated with esophagitis ...[more]

PMID: 26991123

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Project description:BackgroundWe have carried out a study to determine the scope for reducing heart doses in photon beam radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC).Materials and methodsBaseline VMAT plans were created for 20 LA-NSCLC patients following the IDEAL-CRT isotoxic protocol, and were re-optimized after adding an objective limiting heart mean dose (MDHeart). Reductions in MDHeart achievable without breaching limits on target coverage or normal tissue irradiation were determined. The process was repeated for objectives limiting the heart volume receiving ≥ 50 Gy (VHeart-50-Gy) and left atrial wall volume receiving ≥ 63 Gy (VLAwall-63-Gy).ResultsFollowing re-optimization, mean MDHeart, VHeart-50-Gy and VLAwall-63-Gy values fell by 4.8 Gy and 2.2% and 2.4% absolute respectively. On the basis of associations observed between survival and cardiac irradiation in an independent dataset, the purposefully-achieved reduction in MDHeart is expected to lead to the largest improvement in overall survival. It also led to useful knock-on reductions in many measures of cardiac irradiation including VHeart-50-Gy and VLAwall-63-Gy, providing some insurance against survival being more strongly related to these measures than to MDHeart. The predicted hazard ratio (HR) for death corresponding to the purposefully-achieved mean reduction in MDHeart was 0.806, according to which a randomized trial would require 1140 patients to test improved survival with 0.05 significance and 80% power. In patients whose baseline MDHeart values exceeded the median value in a published series, the average MDHeart reduction was particularly large, 8.8 Gy. The corresponding predicted HR is potentially testable in trials recruiting 359 patients enriched for greater MDHeart values.ConclusionsCardiac irradiation in RT of LA-NSCLC can be reduced substantially. Of the measures studied, reduction of MDHeart led to the greatest predicted increase in survival, and to useful knock-on reductions in other cardiac irradiation measures reported to be associated with survival. Potential improvements in survival can be trialled more efficiently in a population enriched for patients with greater baseline MDHeart levels, for whom larger reductions in heart doses can be achieved.

Project description:BackgroundLymphopenia during radiotherapy (RT) may have an adverse effect on treatment outcome. The aim of this study is to investigate associations between lymphopenia and RT parameters in patients with advanced lung cancer. Moreover, to investigate the prognostic role of lymphopenia, blood protein levels, and treatment and patient-related factors.Material and methodsSixty-two advanced stage non-small cell lung cancer (NSCLC) patients were retrospectively analyzed. Blood counts were available prior to, during, and after RT (3Gyx10). For each patient, a thoracic volume of interest (VOI) -including thoracic soft tissue and trabecular bone- was obtained by applying a CT window of -500 to 1200 HU in the planning CT. Dose parameters from thoracic VOI and other regions including lungs and vertebrae were calculated. Association between risk of lymphopenia ≥ G3 (lymphocytes at nadir according to CTCAE v4.0) and therapeutic parameters was investigated using Logistic regression. Relationships between overall survival (OS) and RT dose parameters, baseline blood counts and protein levels, and clinical factors were evaluated using Log-rank and Cox models.ResultMean thoracic RT dose (odds ratio [OR] 1.67; p = 0.04), baseline lymphocytes (OR 0.65; p = 0.01), and corticosteroids use (OR 6.07; p = 0.02) were significantly associated with increased risk of lymphopenia ≥ G3 in multivariable analysis. Worse OS was associated with high mean thoracic RT dose, high CRP/Albumin, large tumor volume and corticosteroids use (p < 0.05, univariate analysis), but not with lymphopenia ≥ G3. CRP/Albumin ratio > 0.12 (hazard ratio [HR] 2.28, p = 0.03) and corticosteroid use (HR 2.52, p = 0.01) were independently associated with worse OS.ConclusionHigh thoracic RT dose gave a higher risk of lymphopenia ≥ G3; hence limiting dose volume to the thorax may be valuable in preventing severe lymphopenia for patients receiving palliative fractionated RT. Still, lymphopenia ≥ G3 was not associated with worse OS. however, high baseline CRP/Albumin was associated with poorer OS and may carry important information as a prognostic factor of OS in advanced NSCLC receiving palliative RT.

Project description:BackgroundBrain metastases (BM) happen frequently in lung cancer patients and lead to a poor prognosis as well as a lower quality of life. The aim of this study was to identify risk factors for BM in locally advanced non-small cell lung cancer (LA-NSCLC) patients receiving radical radiotherapy, which will be useful for selecting appropriate patient population for further intervention and future trial design.MethodsThis was a retrospective cohort study. Patients with inoperable stage IIB-IIIC NSCLC were treated consecutively with definitive thoracic radiotherapy from January 2018 to December 2021, and were retrospectively reviewed and enrolled. Patients with various clinical variables were analyzed to clarify their impact on BM with competing risk models by Fine and Gray.ResultsA total of 134 patients were enrolled in this study. The median follow-up for all patients was 37 months [95% confidence interval (CI): 30.5-43.5 months]. BM occurred in 25 patients at the time of analysis. The 1-year and 3-year cumulative BM incidence were 10.5% and 19.9%, respectively. Patients with BM had worse overall survival than those without BM [stratified hazard ratio (HR) for death: 2.83; 95% CI:1.31-6.11; P<0.001]. Based on univariate analyses, non-squamous cell carcinoma (non-SCC), biological effective dose (BED) and planning target volume (PTV) were used as input variables in multivariable analysis (P<0.01). According to multivariate analysis, non-SCC (P<0.001; HR: 6.08; 95% CI: 2.26-16.37), BED <72 Gy (P=0.017; HR: 2.81; 95% CI: 1.20-6.57), and PTV >157.73 cm3 (P=0.043; HR: 2.56; 95% CI: 1.03-6.35) were independent risk factors for BM. In subgroup analysis of adenocarcinoma with known epidermal growth factor receptor (EGFR) mutation status, PTV >157.73 cm3 and positive EGFR mutation were independent predictors for BM.ConclusionsIn this retrospective study, we found that BED <72 Gy and PTV >157.73 cm3 were significantly associated with BM development and we validated that non-SCC and positive EGFR mutation were risk factors for BM. More research is required to screen the high-risk patient population.

Project description:BackgroundThe dose distribution of carbon ion radiotherapy (CIRT) for locally advanced non-small cell lung cancer (LANSCLC) is highly sensitive to anatomical changes.PurposeTo demonstrate the dosimetric benefits of adaptive CIRT for LANSCLC and compare the differences between patients with and without adaptive plans based on dosimetry and clinical effect factors.Materials and methodsOf the 98 patients with LANSCLC receiving CIRT, 31 patients underwent replanning following re-evaluations that revealed changes that would have compromised the dose coverage of the target volume or violated dose constraints. Dosimetric parameters and clinical factors were compared between patients with and without adaptive plans. Multivariate analysis identified factors influencing the adaptive planning.ResultsThe median number of fractions delivered using adaptive plans was eight (range: 2-18). Adaptive plans ensured target coverage, and the maximum spinal cord dose was significantly decreased (p = 0.02). The median reduction in the maximum spinal cord dose was 10.4 Gy (relative biological effectiveness). Patients with adaptive plans had larger tumor volumes (p < 0.001); the median initial internal gross tumor volumes (iGTVs) of patients with adaptive and nonadaptive plans were 125.9 and 49.79 cm3 , respectively. Tumor volumes of patients with adaptive plans were altered to a greater extent (p < 0.001); the median absolute percentage of volume changes in patients in the adaptive and in nonadaptive groups were 20.76% and 3.63%, respectively, while the median movements of iGTV centers were 5.75 and 2.44 mm, respectively. Binary logistic regression analysis revealed that the iGTV volume change and iGTV center movements were significantly different between the groups.ConclusionsAn adaptive plan can effectively ensure target area coverage and protect normal tissues, especially in patients with large tumor volumes and substantial changes. iGTV volume changes and iGTV center movements are the main factors influencing adaptive planning. Weekly simulation computed tomography scans are necessary for treatment evaluation in patients with LANSCLC treated with CIRT.

Dataset Information

MiRNA-Related Genetic Variations Associated with Radiotherapy-Induced Toxicities in Patients with Locally Advanced Non-Small Cell Lung Cancer.

Publications

MiRNA-Related Genetic Variations Associated with Radiotherapy-Induced Toxicities in Patients with Locally Advanced Non-Small Cell Lung Cancer.

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