Radiation Pneumonitis Research Articles

Different benefits of adaptive radiotherapy for different histologies of NSCLC

Background Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most frequent histological subtypes of non-small cell lung cancer (NSCLC). The aim of this study was to investigate how patients with AC and SCC benefit from image-guided adaptive radiotherapy (ART) with tumour match. Material and methods Consecutive patients diagnosed with AC or SCC of the lung treated with definitive chemo-radiotherapy before and after the implementation of ART and tumour match were retrospectively included for analyses. Data collection included baseline patient and treatment characteristics in addition to clinical data on radiation pneumonitis (RP), failure, and survival. Patients were divided into four categories based on their histology and treatment before (n = 173 [89 AC and 84 SCC]) and after implementation of ART (n = 240 [141 AC and 99 SCC]). Results Median follow-up was 5.7 years for AC and 6.3 years for SCC. Mean lung dose decreased for both histologies with ART, whereas mean heart dose only decreased for patients with AC. Incidences of grade 3 and 5 RP decreased for both histologies with ART. Loco-regional failure (LRF) rates decreased significantly for patients with SCC after ART (p = .04), no significant difference was observed for AC. Overall survival (OS) increased significantly for SCC after ART (p < .01): the 2-year OS increased from 31.0% (95% confidence interval [CI] [22.5–42.6]) to 54.5% (95% CI [45.6–65.3]). No significant effect on OS was observed for patients with AC. Conclusion ART and tumour match in the radiotherapeutic treatment of patients with locally advanced NSCLC primarily led to decreased LRF and improved OS for patients with SCC.

Treatment options for stage III-N2 pulmonary lymphoepithelioma-like carcinoma: A retrospective cohort study

Background and purposePulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare form of non-small cell lung carcinoma (NSCLC) that shares similarities with nasopharyngeal carcinoma. The optimal treatment for stage III-N2 PLELC remains controversial. Methods and materialsWe conducted a retrospective analysis from stage III-N2 PLELC patients between 2009 and 2022 in our center. The patients were categorized into three groups: Group 1 (G1, definitive chemoradiotherapy), Group 2 (G2, radical surgery plus adjuvant chemoradiotherapy), and Group 3 (G3, radical surgery plus adjuvant chemotherapy). ResultsA total of 103 patients were included in the study, with 34, 25, and 44 patients in G1, G2, and G3, respectively. The median follow-up time was 47.4 months. The overall median PFS was 66.6 months, with 3-year PFS and 3-year OS rates of 66.0% and 92.4%, respectively, for all patients. Multivariate analysis revealed no significant difference in PFS between G1 and G2 (p = 0.354), while both groups exhibited significantly longer PFS than G3 (p < 0.001; p = 0.039). Similarly, no significant difference in OS was observed between G1 and G2 (p = 0.649), but both tended to demonstrate improved OS compared to G3 (p = 0.081; p = 0.092). Only one case of grade 3 radiation esophagitis was observed in G1, and no grade 3 or higher radiation pneumonitis were reported. ConclusionsPatients with stage III-N2 PLELC have a favorable prognosis, with radiotherapy playing a crucial role in treatment. Both definitive chemoradiotherapy and radical surgery followed by chemoradiotherapy demonstrate favorable efficacy and manageable toxicity.

Analysis of the risk factors of radiation pneumonitis and the predictive ability of dosiomics in non-small-cell lung cancer.

Purpose: This prospective study investigated the incidence of radiation pneumonitis (RP) after immunotherapy followed by radiotherapy in non-small-cell lung cancer, analyzed the risk factors for RP, and explored the predictive performance of dosimetry and dosiomics. Methods & materials: Risk factors for grade ≥2 RP were calculated by using a logistic regression model. Predictive performance was compared on the basis of area under thecurvevalues. Results: Grade ≥2 RP occurred in 16 cases (26.7%). The AUC values of V5Gy, gray-level dependence matrix-small dependence high gray-level emphasis (GLDM-SDHGLE)and combined features were 0.685, 0.724and 0.734, respectively. Conclusion: Smoking history, bilateral lung V5Gyand GLDM-SDHGLE were independent risk factors for RP. Dosiomics can effectively predict RP.

Comparison of photon intensity modulated, hybrid and volumetric modulated arc radiation treatment techniques in locally advanced non-small cell lung cancer

Background and purposeThere is no consensus on the best photon radiation technique for non-small cell lung cancer (NSCLC). This study quantified the differences between commonly used treatment techniques in NSCLC to find the optimal technique. Materials and methodsTreatment plans were retrospectively generated according to clinical guidelines for 26 stage III NSCLC patients using intensity modulated radiation therapy (IMRT), hybrid, and volumetric modulated arc therapy (VMATC, and VMATV5 optimized for lower lung and heart dose). Plans were evaluated for target coverage, organs at risk dose (including heart substructures) and normal tissue complication probabilities (NTCP). ResultsThe comparison showed significant and largest median differences (>1 Gy or >5%) in favor of IMRT for the mediastinal envelope and heart (maximum dose), in favor of the hybrid technique for the lungs (V5Gy of the total lungs and V5Gy of the contralateral lung) and in favor of VMATC for the heart (Dmean), most of the substructures of the heart, and the spinal cord (maximum dose). The VMATV5 technique had significantly lower heart dose compared to the hybrid technique and significantly lower lung dose compared to the VMATC, combining both advantages in one technique. The mean ΔNTCP did not exceed the 2 percent point (pp) for grade 5 (mortality), and 10 pp for grade ≥2 toxicities (radiation pneumonitis and acute esophageal toxicity), but ΔNTCP was mostly in favor of VMATC/V5 for individual patients. ConclusionThis planning study showed that VMATV5 was preferred as it achieved low lung and heart doses, as well as low NTCPs, simultaneously.

Десятилетние результаты комплексного лечения больных первичным местнораспространенным раком молочной железы

Purpose: To present ten-year results of complex treatment of patients with primary locally advanced breast cancer, depending on the type of ionizing radiation used and chemotherapy regimens. Material and methods: The study included 250 patients with stage T2‒4N0‒3M0 breast cancer, aged 34–69 years (mean age 48.1±5.6 years), who underwent complex treatment (courses of NChT and AChT, hormonal and targeted therapy (according to indications), radical mastectomy and radiation therapy with various types of ionizing radiation) at the Research Institute of Oncology from 2007 to 2020. The mean follow-up period was 10±2.7 years. Main group (n=110) ‒ neutron therapy, comparison group I (n=80) ‒ photon therapy, comparison group II (n=60) ‒ electron therapy. Results: Ten-year relapse-free survival of patients with locally advanced breast cancer (PL BC) after adjuvant neutron therapy on the area of the anterior chest wall was 92.5±3.5 %, after photon therapy ‒ 70.9±5.6 %, after electron therapy ‒ 73.6±7.1 %. There were statistically significant differences between the main group and comparison groups (p&lt;0.05). Overall survival over a ten-year follow-up period in the main group was 87.5±3.8%, in comparison group I ‒ 73.6±8.6 %, in comparison group II ‒ 38.8±10.0 %. Between neutron and electron therapy – p&lt;0.05. In the group with neutron therapy and chemotherapy according to doxorubicin + taxane regimens, ten-year metastatic-free and overall survival was 72.8±10.0 % and 96.7±3.3 %, respectively, compared with neutron therapy and chemotherapy according to FAC/CAF regimens ‒ 44.0±14.7 % and 83.7±6.7 %, respectively (p&lt;0.05). Neutron therapy was well tolerated by all breast cancer patients. Radiation reactions of the skin predominantly I‒II degree. Radiation pneumonitis after neutron therapy ‒ in 6 (5.4 %) out of 110 patients, after photon therapy ‒ in 17 (21.25 %) out of 80 patients with PL BC (p=0.023). Conclusion: Thus, the use of adjuvant neutron therapy in patients with breast cancer T2‒4N0‒3M0 is a safe method and has significantly better results in ten-year relapse-free survival, which makes it possible to increase the effectiveness of complex treatment. In combination with doxorubicin + taxane chemotherapy regimens, neutron therapy increases the 10-year metastatic-free and overall survival rates.

Comprehensive application of bioinformatics analysis and experimental exploration identifying miR-34a/CDK6 axis as the key regulators for radiation-induced lung injury progression

Comprehensive application of bioinformatics analysis and experimental exploration identifying miR-34a/CDK6 axis as the key regulators for radiation-induced lung injury progression

Whole Regional Lymph Node Area Delineation with Deep Learning Model for Total Marrow and Lymphoid Irradiation.

Total body irradiation (TBI) has been performed for conditioning before hematopoietic stem cell transplantation. However, TBI can be related to diverse adverse events including radiation pneumonitis and cataract. Efforts to reduce these events include the total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI). Compared to TMI, TMLI requires more target delineations with lymph nodes which can be labor-intensive and time-consuming. However, with the TMI plans, the coverage to lymph node might be lower than TMLI and its clinical significance is unknown. In the current study, we aimed to develop a deep learning model for automatic delineation of whole regional lymph nodes area and assess the dose coverage of lymph nodes with TMI plans. Whole regional lymph nodes (cervical, axillary, mediastinal, para-aortic, common iliac, external iliac, internal iliac, obturator, presacral, inguinal lymph nodes) were manually contoured by 3 radiation oncologists in 26 patients having whole body computed tomography (CT) images. Twenty patients were designated as the training/validation set and 6 patients as the testing set, and model was developed using the 'nnUNET' framework. The trained model was evaluated with dice coefficient score (DCS), precision, and recall. In addition, dose coverage of the automatically or manually delineated lymph nodes in TMI plans was calculated. The mean value of DCS, precision, and recall of the trained model was 0.76, 0.81, and 0.74, respectively. Dose parameters for manually delineated lymph nodes in previously treated TMI plans showed the mean value of V100% (the percentage of volume receiving 100% of the prescribed dose), V95%, and V90% to be 46.50%, 62.12%, and 73.68%, respectively. The highest V90% was observed in presacral (93.61%), axillary (90.40%), obturator (88.78%), and internal iliac lymph nodes (84.67%). In contrast, the lowest V90% was identified in inguinal (47.95%), cervical (61.69%), and para-aortic (65.75%) and external iliac lymph nodes (68.97%). For automatically delineated lymph nodes, the mean value of V100%, V95%, and V90% of TMI plan was 38.35%, 55.06%, and 67.84%, respectively. The difference with dose coverage of lymph node between delineated manually and automatically was not statistically significant. Automatic delineation of lymph node using deep learning showed the potential to reduce the labor-intensive process of TMLI. When treated with TMI, the coverage of inguinal, cervical, para-aortic and external iliac lymph nodes was lower than expected.

Association of Artificial Intelligence-Screened Interstitial Lung Disease with Radiation Pneumonitis and Mortality in Locally Advanced Non-Small Cell Lung Cancer

Radiation pneumonitis (RP) is a common and dose-limiting toxicity following radiotherapy for non-small cell lung cancer (NSCLC). Patients with interstitial lung disease (ILD) are believed to be at increased risk of developing complications including RP, ILD progression, or death. An automated method to identify patients prior to radiotherapy at high risk of developing toxicities or death may allow clinicians to mitigate risk through informed treatment planning and careful patient monitoring. All locally advanced NSCLC patients treated with definitive radiation from 2006-2021 with a minimum 1 year of follow-up were assessed. RP and mortality data were prospectively collected and retrospectively reviewed. A convolutional neural network (CNN) was previously developed and validated to identify patients with radiographic ILD using planning computed tomography (CT) images, with an accuracy of 0.82. Planning CT scans for the retrospective cohort were used as input to the CNN, with artificial intelligence-screened ILD (AI-ILD) score as an output. AI-ILD scores above our established threshold were labeled as AI-ILD+. The association between AI-ILD score, AI-ILD+/-, mean lung dose (MLD), and the primary outcome of grade ≥2 (G2+) RP or mortality, as well as the secondary outcomes of G2+ RP and mortality were assessed using Wilcoxon rank sum test, univariate and multivariable logistic regression, and Kaplan-Meier survival analysis. Of 799 patients reviewed, 745 eligible patients were included in the analysis; grade 0-5 RP was reported in 51.3%, 27.1%, 16.9%, 4.0%, 0.1%, and 0.5% of patients respectively. Overall, 22.9% of patients were AI-ILD+, and therefore at high risk (>20% chance) of having true ILD. On UVA, AI-ILD score, AI-ILD+ and MLD were significantly associated with the primary outcome of G2+ RP or mortality, as well as the secondary outcome of mortality. However, only MLD was significantly associated with the secondary outcome of G2+ RP. On MVA, both AI-ILD+ (OR 1.42, 95% CI 1.02-1.97, p = 0.04) and MLD (OR 1.13, 95% 1.05-1.21, p = 0.008) were significantly associated with G2+ RP or mortality. On Kaplan-Meier analysis, the median toxicity-free survival (TFS) time for AI-ILD+ and AI-ILD- patients were 1.7 and 3.4 years respectively, with a 2-year TFS of 48.3% vs. 59.3% (log-rank test: p = 0.02). There was no significant difference in rates of G2+ RP. The AI-ILD algorithm can detect high risk patients with significantly decreased TFS following definitive treatment for NSCLC. AI-ILD classification was not associated with a significant difference in rates of RP when accounting for MLD. Future work will focus on improving the classification algorithm, expert radiologist validation of this dataset, and exploring reasons for the mortality difference in AI-ILD+ patients.

STING-Dependent Sensing of Self-DNA Driving Pyroptosis Contributes to Radiation-Induced Lung Injury

Radiation therapy (RT) is indispensable for managing thoracic carcinomas. However, its application is limited by radiation-induced lung injury (RILI), one of the most common and fatal complications of thoracic RT. Nonetheless, the exact molecular mechanisms of RILI remain poorly understood. To elucidate the underlying mechanisms, various knockout (KO) mouse strains were subjected to 16 Gy whole-thoracic RT. RILI was assessed by qRT-PCR, ELISA, histology, western blot, immunohistochemistry, and CT examination. To perform further mechanistic studies on the signaling cascade during the RILI process, pulldown, CHIP, and rescue assays were conducted. We found that the cGAS-STING pathway was significantly upregulated after irradiation exposure in both the mouse models and clinical lung tissues. Knocking down either cGAS or STING led to attenuated inflammation and fibrosis in mouse lung tissues. NLRP3 is hardwired to the upstream DNA-sensing cGAS-STING pathway to trigger of the inflammasome and amplification of the inflammatory response. STING deficiency suppressed the expressions of the NLRP3 inflammasome and pyroptosis-pertinent components containing IL-1β, IL-18, and cleaved caspase-1. Mechanistically, interferon regulatory factor 3, the essential transcription factor downstream of cGAS-STING, promoted the pyroptosis by transcriptionally activating NLRP3. Moreover, we found that RT triggered the release of self-dsDNA in the bronchoalveolar space, which is essential for the activation of cGAS-STING and the downstream NLRP3-mediated pyroptosis. Of note, Pulmozyme, an old drug for the management of cystic fibrosis, was revealed to have the potential to mitigate RILI by degrading extracellular dsDNA and then inhibiting the cGAS-STING-NLRP3 signaling pathway. These results delineated the crucial function of cGAS-STING as a key mediator of RILI, and described a mechanism of pyroptosis linking cGAS-STING activation with the amplification of initial RILI. These findings indicate that the dsDNA-cGAS-STING-NLRP3 axis might be potentially amenable to therapeutic targeting for RILI.

Molecular Imaging of Radiation-Induced Lung Injury Using [18F]AlF Labeled Polypeptide Targeting C-X-C-Chemokine-Receptor-Type-4

Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy (RT) for thoracic malignancies and we currently lack established means for the early detection of RILI. In this study, we synthesized a new tracer, [18F]AlF-NOTA-QHY-04, targeting C-X-C-chemokine-receptor-type-4 (CXCR4) and investigated the feasibility of using this tracer in positron emission tomography combined with computed tomography (PET/CT) for detecting RILI. An RILI model was established using a high-dose single RT (50 Gy/Fraction) to the right lung of female Wistar rats. Experimental animals were scanned with [18F]AlF-NOTA-QHY-04 PET/CT and [18F]FDG PET/CT at various time-points post-RT. MicroCT imaging was conducted weekly till 11 weeks post-RT. Dynamic, competition, autoradiography and histopathological studies were performed on day 14 post-RT. Biodistribution study was further performed on day 18 post-RT. Lung QHY-04 uptake was analyzed in twelve patients with radiation pneumonia, developed during or after thoracic RT. The yield of [18F]AlF-NOTA-QHY-04 was 28.5-43.2%, and the specific activity was 27-33 GBq/μmol. Significantly increased [18F]AlF-NOTA-QHY-04 uptake in the damaged lung compared with that in the normal lung was observed in the experimental animal model on 6 post-RT and peaked on day 14 post-RT (0.96 ± 0.06 vs. 0.50 ± 0.05 %ID/mL, P<0.05), whereas no apparent uptake of [18F]FDG was shown on day 7 and 15 post-RT. Significant intense [18F]AlF-NOTA-QHY-04 uptake was confirmed by autoradiography. No significant difference in CT density was observed between the damaged and normal lung tissues until six weeks post-RT. Immunofluorescence staining demonstrated expression of CXCR4 was significantly increased in the damaged lung tissue, which correlated with results obtained from hematoxylin-eosin and Masson's trichrome staining. Maximum standardized uptake values (SUVmax) were significantly higher in the irradiated lung compared with that in the normal lung in 12 patients with radiation pneumonia (3.07 ± 0.86 vs. 0.585 ± 0.17, P<0.001). SUVmax of patients with grade 2 RILI was significantly higher than that of patients with grade 1 RILI (3.30 ± 0.65 vs. 1.64 ± 0.08, P<0.05). This study indicated that [18F]AlF-NOTA-QHY-04 PET/CT imaging can detect RILI noninvasively and earlier than [18F]FDG PET/CT in a rat model. Clinical studies verified its' feasibility, suggesting the clinical potential of [18F]AlF-NOTA-QHY-04 as a PET/CT tracer for early monitoring of RILI.

Risk Factors for Symptomatic Radiation Pneumonitis after Stereotactic Body Radiotherapy (SBRT) for Early-Stage Lung Cancer

To identify risk factors for symptomatic radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT) in patients with early-stage lung cancer. We reviewed patients with clinical stage IA1-IIA non-small cell lung cancer treated by SBRT in our institution. The primary endpoint was grade ≥ 2 RP. To evaluate the relationship between clinical risk factors and grade ≥ 2 RP, the Gray test was used for univariate analysis and the Fine-Gray model for multivariate analysis. Dose parameters were univariate analyzed using the Fine-Gray model. Optimal thresholds for dose parameters were tested using receiver operating characteristic (ROC) curves. Among a total of 244 patients analyzed. The median age of patients was 77 years. The median follow-up period was 48 months. The 4-year cumulative incidence of grade ≥ 2 RP was 15.3% for all patients. In univariate analysis, tumor size (p = 0.01), central tumor (p < 0.001), interstitial pneumonia (p = 0.002), biological effective dose (BED, α/β ratio of 10 Gy) (p = 0.017), lung volume (%) receiving at least 8 Gy (V8) (p = 0.012), V10 (p = 0.011), V20 (p = 0.022) and mean lung dose (MLD) (p = 0.014) were significantly associated with the risk of grade ≥ 2 RP. In multivariate analysis, central tumor (hazard ratio [HR], 3.77; 95% confidence interval [CI], 1.88-7.55; p < 0.001) and interstitial pneumonia (HR, 4.88; 95% CI, 1.77-13.43; p = 0.002) were significantly associated with the risk of grade ≥ 2 RP. ROC curve analysis showed that the optimal diagnostic thresholds for lung V8, V10, V20, and MLD were 19.5% (the area under the curve [AUC]-0.629), 16.7% (AUC-0.629), 7.9% (AUC-0.621), and 5.2 Gy (AUC-0.623). The incidence of RP2 was found to be significantly high for values higher than the ROC threshold. The 4-year cumulative incidence of grade ≥ 2 RP in the V10 ≤ 16.7% vs V10 > 16.7% groups were 10% vs. 27% (p = 0.0013). Central tumor and interstitial pneumonia were significant risk factors for RP2 after SBRT. We recommend that lung V10 be kept below 16.7%.

Frequent Friers: Outcomes in Patients Who Receive Multiple Courses of Lung SBRT

Stereotactic body radiation therapy (SBRT) is a definitive therapy for early-stage non-small cell lung cancer and solitary pulmonary metastases with high tolerability and excellent survival rates. With longer survival and patients developing subsequent primaries or oligometastatic disease, patients are receiving multiple repeat lung SBRT courses. This study aims to assess safety and efficacy of high-frequency SBRT (HF-SBRT) to the lung, defined as >3 courses. A retrospective review was performed of patients who received >3 courses of lung SBRT. Logistic regression was performed to identify predictors of radiation pneumonitis (RP) and worsening pulmonary function (WPF). Local control (LC) and overall survival (OS) were evaluated using the Kaplan-Meier method. Ninety-four courses of HF-SBRT to the lung were identified among 28 patients. 78% of patients received 3 SBRT courses, 12% received 4 courses, and 7.1% received >5 courses. Median follow-up was 4.4 years. Median age at time of treatment was 73 years-old; 58% males; 42% had an underlying pulmonary comorbidity; 39% prior lung surgery; 52% history of cardiac disease; 52% prior tobacco use; median ECOG 0. Median SBRT dose was 48 Gy. Median interval between courses was 5.6 months. Zero patients experienced greater than grade 2 acute CTCAE v5 toxicity. 7.2% (7) of patients developed RP at median time of 2.6 months [IQR: 1.4,7.4]; grade 1: 3 patients, grade 2: 1 patient, grade 3: 2 patients. Of patients who developed RP, 42% (3) went on to receive further SBRT without experiencing significant adverse events (AEs). History of pulmonary disease, prior lung surgery, and history of tobacco use strongly correlated with WPF but not RP (WPF p-values: <0.001, 0.003, <0.001, respectively). History of cardiac disease did not correlate with WPF or RP. Receiving bilateral lung SBRT treatment (vs unilateral) trended towards correlation with WPF (p = 0.06) and RP (p = 0.08). Time between SBRT courses did not significantly differ for those who developed RP (p = 0.62) or WPF (p = 0.42). No individual or plan sum dosimetric constraint (GTV, PTV, unilateral lung V5, lung V10, lung V20, unilateral mean lung dose, or total lung V20) significantly differed in those who experienced RP. WPF correlated with the plan sum unilateral lung V10 (p = 0.05). LC at 1-year was 100%, 1 local failure occurred at 13 months; 2-year OS was 91.7%, median OS 5.4 years. Overall, HF-SBRT was well tolerated. Development of RP did not correlate with a specific individual or plan sum dosimetric parameter, with patients receiving subsequent courses of SBRT without increased AEs. WPF increasingly occurred with subsequent SBRT courses and correlated with unilateral plan sum V10. This study suggests that in appropriately selected patients, SBRT after RP can still be provided as definitive care, while further studies should validate this and focus attention on mitigating long-term WPF in patients who receive HF-SBRT.

The Role of CT-Based Radiomics Nomogram in Differential Diagnosis of Immune Checkpoint Inhibitor-Related Pneumonitis from Radiation Pneumonitis for Patients with ESCC

The combination of immunotherapy and chemoradiotherapy has widely used for patients with esophageal squamous cell carcinoma (ESCC) and induced treatment-related adverse effects, particularly immune checkpoint inhibitor-related pneumonitis (CIP) and radiation pneumonitis (RP). The aim of this study is to differentiate between CIP and RP by the CT radiomics and clinical or radiological parameters. A total of 76 ESCC patients with pneumonitis were enrolled in this retrospective study and divided into training dataset (n = 53) and validation dataset (n = 23). A total of 837 radiomics features were extracted from regions of interest (ROIs) based on the lung parenchyma window of CT images. A radiomics signature was constructed on the basis of the predictive features by the least absolute shrinkage and selection operator (LASSO). A logistic regression was applied to develop radiomics nomogram. Receiver operating characteristics (ROC) curve and area under the curve (AUC) were applied to evaluate the performance of pneumonitis etiology identification. No significant difference was detected between training dataset and validation dataset. The radiomics signature which was made up of four radiomics features shown a favorable performance on differentiating between CIP and RP with the α-binormal-based and empirical AUC = 0.831 and 0.843. Patients with RP had a close relationship with location (p = 0.003) and shape of lesions (p = 0.002). The nomogram that combined with radiomics signature and clinical factors improved the classifying performance on discrimination in the training dataset (AUCαbin = 0.963 and AUCemp = 0.964). The results were verified in the validation dataset with AUC = 0.967 and 0.964. CT-based radiomics features have potential values for differentiating between patients with CIP and RP. Addition of bilateral changes and sharp border produced superior model performance on classifying, which could be a useful method to improve related clinical decision-making.

Predictive Modeling of Radiation Pneumonitis Induced by Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer Using Radiomics and Clinical Features

The purpose of this study is to establish a prediction model for the development of grade 2 or higher radiation pneumonitis (RP) using radiomics analysis of pretreatment CT images, PET images, and dose distribution, in addition to clinical factors, in patients with locally advanced non-small cell lung cancer (NSCLC) treated with radical chemoradiotherapy. We retrospectively evaluated 128 cases of locally advanced NSCLC treated with radical radiotherapy at our institution from 2008 to 2021. Clinical factors included age, sex, performance status (PS), KL-6, smoking history, histological type, clinical stage, and total radiation dose. Radiomics analysis was performed by analyzing treatment planning CT images, PET images, and dose distribution, and Rad-score (Radiomics-score) was calculated for the extracted features using Lasso-Cox regression. Rad-score (Radiomics-score) was calculated by Lasso-Cox regression for the extracted features. Risk factors were selected by univariate/multivariate analysis of clinical factors and Rad-score. Three models for predicting RP were developed from the identified risk factors using Nomogram: Clinical, Rad-score, and Combined model. The model was evaluated using area under the curve (AUC) based on receiver operating characteristic (ROC) curves and concordance index (C-index). RP was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The cumulative incidence of Grade 2 or higher RP was evaluated using the Kaplan-Meier method. Of the 128 cases, grade 2 or higher RP was observed in 50 cases (39%). Regarding clinical factors, gender, smoking status, and histology were selected as significant predictors of RP. Lasso-Cox analysis of radiomics features selected 11 features from CT images, 7 features from PET images, and 16 features from dose distribution as predictors of RP, yielding a total of 34 factors. The combined model (C-index: 0.96, AUC: 0.92) showed the best discrimination performance compared to the clinical model (C-index: 0.73, AUC: 0.56) and the Rad-score model (C-index: 0.87, AUC: 0.92). Risk classification using the combined model showed that the 1-year cumulative incidence of grade 2 or higher RP was 65% in the high-risk group, significantly higher than 15% in the low-risk group (p<0.001). The combined model with Rad-score and clinical factors can predict grade 2 or higher RP in NSCLC patients with high accuracy.

Association of Single Nucleotide Polymorphisms in Transforming Growth Factor-β1 Pathway and Risk of Radiation Pneumonitis in Lung Cancer Patients Treated with Thoracic Radiation Therapy

Several clinical and dosimetric parameters are known to be associated with radiation-induced lung toxicity, including radiation pneumonitis (RP). Also, single nucleotide polymorphisms (SNPs) of genes in TGF-β1 pathway have a notable association with the RP. However, studies on the predictive value of SNPs for RP are still limited. Herein, we tried to develop a novel integrated predictive model for severe RP in lung cancer patients. A total of 59 patients who were treated with definitive or preoperative radiotherapy for primary lung cancer and had DNA samples were included. Potentially functional and tagging SNPs of TGF-β1 (rs1800469, rs1800471, rs1982073, and rs11466345), BMP2 (rs235768, rs3178250, rs1979855, and rs170986), and BMP4 (rs17563, rs4898820, and rs762642) were genotyped. Logistic regression was performed to build severe (grade ≥2) RP prediction models, and best subset selection algorithm with L0 and L2 regulations was used for variable selection. Only clinical/dosimetric variables were evaluated in model 1, and those variables as well as SNPs were included in model 2. Using beta coefficient obtained by the logistic regression, a scoring system was also developed. With median follow-up of 39.7 months, severe RP occurred in 20.3% of patients. In model 1, age (>66) and PTV volume (≥300 cc) were significant factors (p = 0.016, OR 8.820 [95% CI, 1.730-63.800]; and p = 0.024, OR 7.440 [95% CI, 1.460-52.100], respectively). In model 2, the above two factors (p = 0.010, OR 16.200 [95% CI, 2.440-187.000] and p = 0.025, OR 10.100 [95% CI, 1.610-105.000]) and the AG/GG genotype in BMP2 rs1979855 were significant factors (p = 0.031, OR 7.260 [95% CI, 1.380-59.100]). The AUC was significantly higher in model 2 than in model 1 (0.822 vs. 0.741, p = 0.029). According to developed scoring system, patients with a score >2.8 are more likely to experience severe RP (AUC 0.829). BMP2 rs1979855 could serve as a reliable biomarker for predicting RP while significantly improving predictive power compared to when only clinical factors were used.

Handcrafted Radiomics, Deep Learning Radiomics in the Prediction of Radiation Pneumonitis for NSCLC Patients Treated with Immunotherapy Followed with Thoracic Radiotherapy

Our previous study has shown that NSCLC patients previously received immune checkpoint inhibitors (ICIs) underwent thoracic intensity modulated radiotherapy have a higher risk of acute radiation pneumonitis (RP). This study aimed to establish machine learning models using handcrafted radiomics (HCR), deep learning-based radiomics (DLR) and clinical characteristics to improve the prediction of symptomatic radiation pneumonitis (RP) (grade ≥ 2) status for NSCLC patients treated with immunotherapy followed with thoracic radiotherapy. This study retrospectively collected data of 61 NSCLC patients meeting the requirements of study enrollment. Of these 61 patients, 35 developed symptomatic graded ≥ 2 RP. We defined 3 regions of interest (ROIs) in planning CT images including gross tumor volume (GTV), planning tumor volume (PTV), PTV-GTV. We calculated the mean dose, V5, V10, V20, and V30 within TL-GTV, and the volume of GTV, PTV and total lung. A total of 516 handcrafted radiomics features and 512 deep features were extracted from each 3 ROIs. Person Correlation Analysis and Least Absolute Shrinkage and Selection Operator (LASSO) were used to reduce the dimension of features. The HCR models, DLR models and the fusion models across different ROIs with machine learning classifiers were built and compared. In multi-classifier modeling, models with PTV under logistic regression (LR) classifiers showed better prediction than other ROIs under different machine learning algorithms. Based on PTV with LR, HCR+ DLR model had better performance, with an area under the curve (AUC) of 0.95 (95% confidence interval (CI): 0.893-1) in the training cohort and 0.87 (95% CI: 0.698-1) in the test cohort, which was higher than that of HCR model, with an AUC of 0.86 (95% CI: 0.755-0.9) in the training cohort and 0.82 (95% CI: 0.624-1) in the test cohort, the results of fusion model with HCR, DLR and 7 clinical characteristics including T, N, clinical stage, age, smoking, radiotherapy alone/combined and V30, demonstrated the best distinguishing performance, with an AUC of 0.99 (95% CI: 0.970-1) in the training cohort and 0.91 (95% CI: 0.784-1) in the test cohort. The combination of HCR, DLR and clinical characteristic underwent machine learning algorithms can improve the prediction of symptomatic RP in NSCLC patients treated with ICIs followed with thoracic radiotherapy.

Combining Dosimetric and Radiomics Features for the Prediction of Radiation Pneumonitis in Locally Advanced Non-Small Cell Lung Cancer by Machine Learning

This study aimed to analyze the dosimetric factors and radiomics features of tumor and lungs in locally advanced non-small cell lung cancer (LANSCLC) to establish machine learning models and improve the prediction of grade (G) 2 radiation pneumonitis (RP). This study retrospectively collected data of 284 LANSCLC patients underwent concurrent chemoradiotherapy (CCRT) to a median dose of 64 Gy in 20-33 fractions between 2013 and 2021. Of this cohort, 21.1% of patients had ≥ G2 RP. There were 4 regions of interest (ROIs) had been identified in planning computed tomography images: gross tumor volume (GTV), ipsilesional lung (IL), contralesional lung (CL), and total lung (TL). We calculated the dose-volume histogram (DVH) from the lowest dose to the maximum dose increasing by degrees with 1 Gy, and extracted a total of 172 radiomics features from all the 4 ROIs. We selected the best predictors for classifying 2 groups of patients using a sequential backward elimination support vector machine model. The best predictors for ≥ G2 RP were the combination of 8 radiomics features and 7 dosimetric factors in training group, and the validation group achieved an area under the curve (AUC) of 0.847 (accuracy, 80.38%; sensitivity, 78.95%; specificity, 81.82%). The eight radiomic features included 2 from GTV while 1, 2 and 3 from IL, CL and TL, respectively. For dosimetric factors, V65 of GTV, V20, V50 and V55 of IL, V10 of CL, V20 and V55 of TL appeared to be significantly related to symptomatic RP. These dosimetric factors should be constrained to less than 99.2%, 50.0%, 17.5%, 13.0%, 39.5%, 32.0%, and 6.6%, respectively. Combining dosimetric factors and radiomics features within GTV, IL, CL and TL can improve the prediction of symptomatic RP in LANSCLC patients treated with CCRT. The results suggested the importance of V65 of GTV, V20, V50 and V55 of IL, V10 of CL, V20 and V55 of TL as predictors of symptomatic RP and provide useful information for optimization of treatment planning in the era of combination of radiotherapy and immunotherapy.

Survival Outcomes of Extensive Stage Small Cell Lung Cancer Patients Treated with Consolidative Thoracic Radiotherapy at a Tertiary Cancer Center

Most small cell lung cancer cases present as Stage IV (M1) or extensive stage (ES-SCLC), which are defined as tumor extending outside the hemithorax without a tolerable radiation portal. The CREST trial demonstrated improved local control with a modest overall survival (OS) benefit at the 2-year secondary endpoint of 14% survival with consolidative thoracic radiotherapy (CTRT) compared to 3% without CTRT. Low toxicity rates were also observed. This study reports our institutional ES-SCLC experience for patients treated with CTRT. A retrospective review was conducted on ES-SCLC patients treated with CTRT at our institution between 2014 and 2019. CTRT was defined as ≥30 Gy of thoracic radiotherapy. OS and tolerability of treatment were assessed in this population. Chemotherapy details were also captured. OS rate was determined using the Kaplan-Meier method and the time from start of CTRT to last date of follow-up or death. CTRT tolerability was determined using incidence and grade of esophagitis and radiation pneumonitis as per CTCAE v5. We identified 100 ES-SCLC patients treated with any thoracic RT at our institute, of which 45 received thoracic RT for palliative intent or with <30 Gy. The remaining 55 patients received ≥30 Gy CTRT and were included for analysis. The median age was 65.1 years (range 46.6-86.9) and 36 (65%) were male. The median follow-up for this sample was 0.8 (range 0.03-4.2) years. Median chemotherapy cycles were 6 (range 1-6), most receiving ≥4 cycles (87%) and completing chemotherapy prior to CTRT initiation (91%) with a minority concurrently receiving chemotherapy and CTRT (9%). Platinum chemotherapy was the most common (96%) with 2 patients receiving etoposide alone (4%). The most common CTRT regimens were 30 Gy in 10 fractions (80%) followed by 40 Gy in 15 fractions (9%) and 45 Gy in 30 twice-daily fractions (7%). Most patients (67%) were treated with IMRT/VMAT technique, while the remaining (33%) patients were treated with 3DCRT. The median survival time was 1.3 years with 1- and 2-year OS of 57.2% (CI 44.0 - 74.3%) and 26.1% (CI 12.9 - 52.7%), respectively. CTRT was well tolerated with no grade 4+ toxicities. The most common toxicity was esophagitis with 21 patients (39%), of which 15 were G1 (28%) and 6 were G2 (11%). Radiation pneumonitis was present in 5 patients (9.2%) with 1 G1 (2%), 3 G2 (6%), and 1 G3 (2%) cases. Consolidative TRT for ES-SCLC in this institutional series was at least as good as the reported CREST outcome with modest acute toxicities in this cohort. Disease burden at diagnosis, chemotherapy response, patterns of failure, and subsequent therapies will be further investigated.

Long-Term Results of a Multi-Institutional Study of Dynamic Tumor Tracking-Stereotactic Body Radiotherapy for Lung Tumors

We had conducted a multi-institutional phase II study to evaluate the safety and efficacy of dynamic tumor tracking-stereotactic body radiotherapy (DTT-SBRT) for lung tumors. The primary endpoint was 2-year local control, which was reported to be 95.2%. After the initial evaluation of the primary endpoint, the study was extended as an observational study which was designed to evaluate 5-year survival and late toxicities. We present the long-term results of DTT-SBRT for lung tumors. The main eligibility criteria for the study were as follows: (1) primary or metastatic lung cancer with a diameter of 5 cm or less, and up to 3 lesions without any extrapulmonary lesions; (2) ineligibility to standard surgery, or patient's refusal of surgery; (3) ECOG-PS of 0 to 2; and (4) expected range of respiratory motion of 10 mm or more. The study included 48 patients from four institutions with the median age of 80 years (range, 49-90 years). Forty-two patients had primary non-small-cell lung cancer, and 6 patients had metastatic lung tumors. Forty-eight tumors (median diameter, 23.5 mm; range, 5-47 mm) in 48 patients were targeted for DTT-SBRT using a gimbal-mounted linear accelerator. Prior to treatment planning, spherical gold markers were placed around the tumor to detect internal tumor motion using fluoroscopy. The prescribed dose was 50 Gy in four fractions. Treatment beams were delivered with DTT according to a 4D model that predicts internal tumor motion with abdominal wall motion. DTT-SBRT was successfully delivered to all but one patient who had poor correlation between abdominal wall and tumor motion. Median follow-up period at data cutoff was 5.0 years (interquartile range, 3.1-6.3 years). Twenty-nine patients died; the causes of death were cancer-specific in 10 patients, comorbidity in 14 patients (pulmonary disease, renal failure, cerebral infarction, other malignancies, etc.), and unknown in 5 patients without cancer recurrence. Overall survival at 5 years was 51.5% (95% confidence interval [CI], 36.5-64.6%). Progression-free survival and local control at 5 years were 41.0% (95% CI, 27.0-54.5%) and 92.6% (95% CI, 78.7-97.6%), respectively. There were no grade 4-5 toxicities. One patient (2%) developed grade 3 radiation pneumonitis at 3 months. Grade 2 toxicities were observed in 9 patients (19%), including dyspnea, radiation pneumonitis, pleural effusion, rib fracture, and dermatitis. Dynamic tumor tracking SBRT achieved the long-term efficacy with low incidence of severe toxicities in lung tumors with respiratory motion. In this elderly patient cohort, non-cancer deaths were observed more than cancer-specific deaths.

30 Gy vs. 45 Gy Consolidative Thoracic Radiation (cTRT) for Extensive Stage Small Cell Lung Cancer (ES-SCLC): A Multicenter, Randomized, Phase 3 Trial

Consolidative thoracic radiotherapy (cTRT) showed potential benefit to extensive stage small cell lung cancer (ES-SCLC). However, the optimum dose of cTRT is unknown. The purpose of this randomized trial was to compare the effect of 45 Gy in 15 fractions with 30 Gy in 10 fractions cTRT in ES-SCLC. This phase III, randomized trial was conducted in 12 public hospitals in China. Eligible patients with pathologically confirmed ES-SCLC who responded to 4-6 cycles of etoposide plus cisplatin (EP) or carboplatin (EC) chemotherapy were randomized 1:1 to receive either 30 Gy in 10 fractions or 45 Gy in 15 fractions cTRT. The primary outcome was 2-year overall survival (OS). Secondary outcomes included 2-year progression-free survival (PFS), 2-year local control (LC) and radiation treatment related toxicity. The primary objective was to detect an OS improvement in 45 Gy cTRT group at 2 years from 13% to 26% assuming a two-sided a = 0.05 and power of 85%, with a planned sample size of 186 patients. This trial was registered with Clinical Trials.gov, number NCT02675088. Between January 15, 2016, and September 20, 2022, 90 patients were randomly assigned either 30 Gy in 10 fractions (n = 50) or 45 Gy in 15 fractions (n = 40) cTRT group. Recruitment to the trial closed early due to slow accrual since first-line chemoimmunotherapy has become the new standard of care for ES-SCLC. The median age of patients was 58 years, 87.8% were male, 76.7% had a smoking history, 95.6% received IMRT, and 58.9% received prophylactic cranial irradiation. At a median follow-up of 39.9 months (IQR 27.2-59.2), there was no significant difference in the 2-year OS between the 45 Gy group and the 30 Gy group, at 43.4% (95% CI 29.3%-64.3%) and 40.0% (95% CI 27.9%-59.1%), respectively (log-rank p = 0.62; HR 1.13 [95% CI 0.69-1.84]). The 2-year PFS was 12.1% (95% CI 4.3%-33.8%) in the 45 Gy group and 9.0% (95% CI 3.2%-25.2%) in the 30 Gy group (log-rank p = 0.25, HR 0.76(95% CI [0.478-1.22]). There were also no significant differences in locoregional recurrence free survival (log-rank p = 0.75; HR 0.888 [95% CI 0.423-1.863]) and distant metastasis free survival (log-rank p = 0.95; HR 1.015 [95% CI 0.624-1.651]) between two groups. No grade 5 toxicity was observed in both groups. Patients treated with higher cTRT dose presented with increased incidence of grade 3+ radiation pneumonitis (10% vs 2%) and hematological toxicity (20% vs 12.5%). This randomized trial did not find a higher probability of survival improvement in patients with ES-SCLC receiving cTRT of 45 Gy in 15 fractions compared with 30 Gy in 10 fractions. In contrast, there was an increase in toxicity, especially radiation pneumonitis. Additional randomized studies investigating the role of cTRT in ES-SCLC after a response to chemoimmunotherapy are warranted.