Risk Of Pneumonitis Research Articles

Pneumonitis in Advanced Non-Small Cell Lung Cancer: No Interaction between Immune Checkpoint Inhibition and Radiation Therapy

<h3>Purpose/Objective(s)</h3> Pneumonitis is a common complication of treatment for advanced non-small cell lung cancer (NSCLC). Radiation pneumonitis and immune-related pneumonitis have been studied independently, but little information has emerged on the interactions between radiation therapy (RT) and immune checkpoint inhibition (ICI). In this study, we aim to examine if RT and ICI interact in causing pneumonitis. <h3>Materials/Methods</h3> A retrospective cohort was assembled using the Surveillance, Epidemiology, and End Results-Medicare database, including Medicare beneficiaries diagnosed with American Joint Committee on Cancer 7th ed. (AJCC) stages 3B-4 NSCLC between 2013-2017. Exposures to RT and ICI were determined by evaluating for treatment codes in the 12 months after diagnosis and evaluating for a second exposure (e.g., ICI after RT) within 3 months after the first exposure. A previously validated algorithm for identifying cases of pneumonitis in inpatient and outpatient claims was used to evaluate for the outcome in the 6 months after treatment. Cox regression was performed to estimate hazard ratios of pneumonitis for patients treated with RT, ICI, and both therapies (RT+ICI), relative to a cohort unexposed to RT and ICI. Presence of an additive interaction was determined by computing the relative excess risk due to interaction (RERI) and constructing 95% confidence intervals (95% CI) through bootstrapping. <h3>Results</h3> There were 18,780 patients included in the analysis with 9,345 (49.8%), 7,533 (40.2%), 1,332 (7.1%), and 550 (2.9%) in the control, RT, ICI, and RT+ICI groups. There were more patients with squamous histology and AJCC stage 3B disease in the RT group (p<0.01). The incidence and hazard ratios of pneumonitis are presented in Table 1. The RERIs were -6.1 (95% CI: -13.1–0.6, p=0.97) and -4.0 (95% CI: -10.7-1.5, p=0.91) in the unadjusted and adjusted analyses, respectively, consistent with no evidence of additive interaction (RERI≤0) between RT and ICI. These results were stable when varying the allowable time to be exposed, time to develop pneumonitis, algorithms for identifying pneumonitis, and limiting immortal-time bias through landmark analyses and measuring RT and ICI exposure as time-varying covariates. <h3>Conclusion</h3> In this retrospective study of Medicare beneficiaries with advanced NSCLC, there was no clear synergy between RT and ICI in causing pneumonitis. The risk of pneumonitis in patients treated with RT and ICI is not more than could be expected from each therapy alone. These data support the safety of combining RT and ICI in clinical practice.

Combining Radiomics Features with Immune Response Biomarkers to Build a XGBoost Model to Predict Radiation Pneumonitis (RP) in Patients with Primary Lung Cancer

<h3>Purpose/Objective(s)</h3> Patients are heterogenous in their responses to radiation lung damage. It has been reported mostly from western people that the computed tomography (CT) radiomics features have a potential to identify patients at high risk for radiation pneumonitis (RP) in Western people. The purpose of this study was to 1) validate the significance of radiomics features on RP prediction, 2) exam the differences in systemic level of immune checkpoint indoleamine 2,3-dioxygenase (IDO) in patients with RP and without RP, and 3) explore the performance of the extreme gradient boosting (XGBoost) of combining above factors, on grade 2 and above RP in Chinese patients with primary lung cancer. <h3>Materials/Methods</h3> Planning CT scans and blood of baseline and end of treatment from 43 patients treated for primary lung cancer with radiotherapy were collected. Grade 2 and above RP was defined as cough or short of breath need medication treatment during or at the end of radiotherapy. Radiomics features were extracted from lung-GTV volume in planning CT using python package open-source software. Serum kynurenine, tryptophan and kynurenine: tryptophan ratio, which is IDO systemic activity related biomarkers (IDO biomarker) were measured at pre-RT and end of RT. The relation between features [radiomics features and IDO biomarker] and RP. Finally, the radiomics features with p value smaller than 0.1 were used for modeling. Patients were randomly split into 80% for training and 20% for validation. Model was built with XGBoost in train dataset and was tested in independent test dataset. The model predictive ability was assessed using area under the receiver operating characteristic curve (AUC). <h3>Results</h3> Seven out of 43 (16.3%) patients presented grade 2 and above RP. A total of 109 radiomics features were extracted. A total of 31 features, including 6 first-order, 4 gray level co-occurrence matrix (GLCM), 5 gray level dependence matrix (GLDM), 5 gray level run length matrix (GLRLM), 3 gray level size zone matrix (GLSZM) and 8 shape features, were significantly different (p value ≤ 0.05) between patients with RP and without RP. The IDO biomarkers at pre-RT and end of RT seemed to be non-significant (p value: 0.46-0.81). 43 radiomics features with p values smaller than 0.1 were used for model building. AUC of in the training dataset was 0.86 [95% CI 0.75-1] and of test dataset was 0.75 [95% 0.5-1]. A model of combined IDO biomarkers and radiomics features to build model, The predictive AUC of the training dataset was 0.9 [0.75-1] and of test dataset was 0.75 [0.5-1]. AUC slightly improved on training set. <h3>Conclusion</h3> This study at some degree validated the significance of radiomics features extracted from planning CT on predicting grade 2 and above RP in primary lung cancer in Chinese patients which has not been reported previously. IDO biomarkers did seem help, but the model built with XGBoost approach improved the predictive ability. Study with larger number of patients and ideally from multicenters are needed to validate this finding.

Association between DNA Repair Gene Pathway Polymorphisms and Risk of Radiation Pneumonitis: A Systematic Review and Meta-Analysis

<h3>Purpose/Objective(s)</h3> Radiation pneumonitis is a dose-limiting toxicity of radiotherapy. Genetic variation in this pathway affects post-radiotherapy DNA repair and subsequently the level of toxicity. Previous studies published within this area in lung cancer treatment have been inconsistent. Our meta-analysis therefore aimed at examining the effect of SNPs on radiation pneumonitis of lung cancer patients receiving radiotherapy. <h3>Materials/Methods</h3> We performed a systematic review of relevant studies published on or before 12 October 2021 on PubMed, Scopus, Embase, and Web of Science databases. Studies with genotyping data of lung cancer patients receiving radiotherapy were included. Conference abstracts, reviews, non-English articles, studies in which radiotherapy was used as a neoadjuvant therapy were excluded. Quality assessment was performed using the Newcastle-Ottawa Scale (NOS) by two independent reviewers. We calculated the pooled odds ratios and the 95% confidence intervals to evaluate the association between each DNA repair gene pathway polymorphism and all-grade radiation pneumonitis. The allelic, dominant, recessive, homozygous and heterozygous genotype models were used to assess the association. <h3>Results</h3> 706 studies were initially obtained after database searching and de-duplication. 15 studies (2964 patients) were included in the systematic review. The median follow-up time ranged from 3 months to 39.5 months. Under the allelic model, the G allele for NEIL1 gene was significantly associated with a reduced odds of developing radiation pneumonitis compared to the C allele for rs7402844 (OR 0.70, 95% CI: 0.49, 0.99, P = 0.04, I-square = 0%, total number of patients: 341). Similarly, the T allele for APE1 gene was significantly associated with a reduced odds of developing radiation pneumonitis compared to the G allele for rs1130409 (OR 0.59, 95% CI: 0.43, 0.81, P = 0.001, I-square = 0%, total number of patients: 432). Other SNPs were found to have no significant associations with all-grade radiation pneumonitis. <h3>Conclusion</h3> This systematic review and meta-analysis showed that two SNPs in the DNA repair gene pathway are significantly associated with the risks of developing radiation pneumonitis in lung cancer patients. Further cohort studies assessing a combination of DNA repair gene polymorphisms with a greater sample size are needed.

Evaluation of Pneumonitis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Receiving Osimertinib and Thoracic Radiotherapy

<h3>Purpose/Objective(s)</h3> In epidermal growth factor receptor mutated (EGFR+) metastatic non-small cell lung cancer (mNSCLC), pneumonitis is a known side effect independently associated with both Osimertinib and thoracic radiotherapy (TRT). The objective of this study was to examine the relationship between concurrent Osimertinib and TRT with regards to pneumonitis, and to observe patterns of practice regarding the cessation of Osimertinib during TRT. <h3>Materials/Methods</h3> In this single institution retrospective cohort study between 2016 and 2020, patients with EGFR+ mNSCLC who received both Osimertinib and TRT were included. TRT was defined as any course of radiotherapy that involved lung parenchyma within the treated field. The primary endpoint was the incidence of symptomatic (CTCAE grade ≥ 2) pneumonitis. Comparisons were made with multivariable Cox proportional hazards regression for both grade ≥ 2 and any grade pneumonitis. <h3>Results</h3> Of the 151 patients receiving Osimertinib during the study period, 41 underwent 147 courses of radiation either during or within 6 months of Osimertinib initiation, with 68 (46.3%) lesions treated with TRT. In total, 5 patients developed RT-related symptomatic pneumonitis (12.2%), of which 1 was grade 4 and another grade 5. Mean (±SD) age at TRT was 65.5 (±12.0) years. Most patients had de novo metastatic disease (n=31; 75.6%), adenocarcinoma histology (n=38; 92.7%), and 16 (39%) were on Osimertinib as first line systemic therapy. The mean (±SD) number of cycles of Osimertinib was 9.6 (±4.3). Median total dose and fractionations were 20 Gy (interquartile range [IQR]: 20-30 Gy) and 5 (IQR: 1-5), respectively. During TRT, Osimertinib was knowingly held in 12 patients (29.3%), most commonly for 1-2 days before and after (n=7; 17.1%) the course of treatment. Osimertinib was knowingly continued during TRT for 5 patients (12.2%), and in 8 patients (19.5%) it was not documented whether the medication was held. Multivariable analysis identified that each additional cycle of Osimertinib was associated with an increased incidence of grade ≥ 2 pneumonitis (hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.15-2.07, p=0.004). Total radiation dose was also associated with increased incidence of any grade of pneumonitis (HR per 5 Gy: 1.38, 95% CI: 1.03-1.86, p=0.031). There was no association with incidence of pneumonitis (any grade) if Osimertinib was continued during TRT (HR: 3.36, 95% CI: 0.13-86.56, p=0.47) or if TRT was given within 6 months of Osimertinib initiation (HR: 0.20, 95% CI: 0.02-2.21, p=0.19). <h3>Conclusion</h3> In patients with EGFR+ mNSCLC treated with Osimertinib and TRT, the risk of symptomatic pneumonitis was moderate, and in 2 instances serious. Patterns on whether to hold Osimertinib during TRT, and for how long, were variable. Symptomatic pneumonitis with TRT was associated with prolonged Osimertinib use. Further research is required to further clarify the safety of the combination of these two treatment modalities.

Incidence of Radiation Pneumonitis after a Single 550 cGy Fraction of Total Body Irradiation: Single Institutional Experience

<h3>Purpose/Objective(s)</h3> Total body irradiation (TBI) is an important component of the conditioning regimen prior to allogeneic stem cell transplant. While a variety of TBI dose and fractionation schemas have been studied, the optimal regimen is unknown. The American College of Radiology (ACR) suggests that relatively low dose rates of less than 10-20cGy per minute may provide the optimal outcome and reduce the risk of interstitial pneumonitis. However, there are no reported outcomes of patients treated with dose rates higher than 20cGy per minute to the best of our knowledge. The objective of the study is to investigate the incidence of radiation pneumonitis after a single fraction of 550 cGy TBI delivered at a high dose rate (∼30cGy per minute) at a single institution, where this regimen has been used as a component of the conditioning regimen for patients with hematological malignancies undergoing hematopoietic stem cell transplantation over the past 25 years. Radiation pneumonitis (RP) is an important potential toxicity associated with TBI and its incidence has not been previously reported for this regimen. <h3>Materials/Methods</h3> A retrospective chart review was performed for 183 consecutively treated patients (61% male, 39% female, aged 24 to 71) treated with single fraction 550 cGy TBI delivered at a high dose rate at our institution from 2010-2021 for a wide range of hematological malignancies including ALL (n=55), AML (n=49), CLL (n=7), CML (n=4), various forms of lymphoma (n=49), MDS (n=8), multiple myeloma (n=7), T-PLL (n=2), and B-PLL (n=2). Patients received one of the following conditioning regimens: 550 cGy single fraction TBI with cyclophosphamide, 550 cGy single fraction TBI with cyclophosphamide and thymoglobulin, or 550 cGy single fraction TBI with cyclophosphamide and fludarabine. Patients were treated on a stretcher with opposed lateral fields. Patients were evaluated for the development of radiation pneumonitis at 12 months based on CTCAE v5.0. <h3>Results</h3> Of the 183 patients, 96 patients survived until the 12-month time point. The cause of death includes sepsis, GVHD, and multi-organ failure, among others. The incidence of grade 2 or greater RP was 9.4% (9/96 patients) at 12 months in these patients. Only 1 patient developed grade 3 RP and 1 patient developed grade 4 RP. <h3>Conclusion</h3> The institutional regimen of 550 cGy TBI delivered in a single fraction at a high dose rate is associated with a low incidence of radiation pneumonitis at 12 months; however, the analysis was limited by competing transplant-related mortality in this patient population.

Evaluation of Repeated Lung Stereotactic Body Radiotherapy Using a Radiotherapy Dose Accumulation Routine

<h3>Purpose/Objective(s)</h3> Repeated lung SBRT has been used for recurrent or metachronous non-small-cell lung cancer. Comprehensive evaluation of cumulative dose is essential for safe reirradiation to minimize the risk of pneumonitis and esophageal toxicity. We evaluated an in-house script named RADAR (Radiotherapy Dose Accumulation Routine) designed to provide accurate dose assessment that accounts for registration uncertainties, and improve the efficiency of clinical workflow. <h3>Materials/Methods</h3> In this pilot study, we analyzed a cohort of 20 patients who underwent 2-5 courses of repeated lung SBRT. Lung volume changed 8±8% between courses. Planning CT images from earlier treatment courses were registered onto the final course in two steps: first, a rigid registration based on alignment of spine and rib cage, then a deformable image registration (DIR) using a ‘demons' algorithm in a planning system. The resulting deformable vector fields were used by RADAR to transform voxels for automated dose accumulation. User can choose to output either physical dose or equivalent dose in 2Gy fractions (EQD2, α/β=3) with a discount factor (Paradis, ARO 2019). RADAR provides three approaches for dose accumulation: 1) direct sum that outputs voxel level dose summation; 2) unrestricted search that incorporates DIR uncertainty by conservatively assigning the maximum dose within a search radius (3mm) to the voxel of interest for dose accumulation; 3) restricted search, which performs the same dose accumulation as in 2) but imposes structure label matching in the search radius, therefore including only voxels within the same structure. Accumulated dose distribution was written back to the planning system for evaluation. We extracted mean lung dose (MLD) and esophagus D5cc (EsoD5cc) with respect to various accumulation approaches for comparison. <h3>Results</h3> MLD and EsoD5cc were significantly higher when accounting for DIR uncertainties (<i>p</i><0.001 two-tailed t-test). MLD has less uncertainty than EsoD5cc due to its averaging nature. For radiotherapy with >2 courses, RADAR considerably shortened the processing time by auto-accumulating dose from multiple courses simultaneously, as opposed to the cumbersome manual approach of creating plan sums iteratively. Typical time for dose accumulation and evaluation using RADAR is < 10 mins. <h3>Conclusion</h3> RADAR is a convenient and efficient tool to calculate and evaluate cumulative dose for lung reirradiation cases. It identifies higher OAR doses due to dose accumulation uncertainties, for example coming from the registration. Our study provides initial data to establish clinical guidance for design and optimization of repeated lung SBRT.

Dose to High Ventilating Lung Predicts Radiation-Induced Pneumonitis in Lung Cancer Patients

<h3>Purpose/Objective(s)</h3> Current lung cancer radiotherapy (RT) planning does not account for regional variation in pulmonary function. Functional avoidance RT is being studied as a technique to limit pulmonary toxicity. There is limited data on useful dose parameters for avoiding high ventilating lung. Our objective was to identify metrics of radiation dose delivered to high ventilating lung predictive of radiation-induced pneumonitis. <h3>Materials/Methods</h3> A combined prospective and retrospective cohort of 108 patients with locally advanced non-small cell lung cancer treated with standard fractionated RT of 60-66 Gy in 30-33 fractions were evaluated. Regional lung ventilation was determined from pre-RT 4-dimensional computed tomography (4DCT) using the Jacobian determinant of a B-spline deformable image registration to estimate lung tissue expansion during respiration. Lung voxels with greater expansion than the voxel-wise population median expansion were defined as high ventilating. Mean dose and volumes receiving dose over thresholds of 5-60 Gy were analyzed for both total lung-ITV (MLD, V5-V60) and high ventilating functional lung-ITV (fMLD, fV5-fV60). The primary endpoint was symptomatic grade 2+ (G2+) pneumonitis. Differences in dose metrics were compared and receiver operator curve (ROC) analyses were used to identify predictors of pneumonitis. <h3>Results</h3> G2+ pneumonitis occurred in 20.4% of patients. There were no differences between stage, smoking, COPD or chemo or immunotherapy use between G<2 or G2+ pneumonitis patients. Total lung median MLD, V5 Gy and V20 Gy were 15.4 Gy, 58.0% and 25.7%, respectively. Each metric was significantly different between patients with G<2 and G2+ pneumonitis (p<0.016). Optimal ROC points predicting pneumonitis from total lung dose were MLD < 17 Gy, V5 < 59% and V20 < 25%. Regional ventilation calculated from 4DCTs had a population-wide median of 18% voxel-level expansion. The median amount of high ventilating (≥ 18% expansion) lung per patient was 52.4% ± 23.0%. All functional dose metrics (fMLD, fV5-fV60) were significantly different between G<2 and G2+ patients (p<0.04). Optimal ROC points of fMLD < 15 Gy, fV5 < 53% and fV20 < 19% of functional lung were predictive of G2+ pneumonitis. Patients with fMLD ≥ 15 Gy had a 41% risk of developing G2+ pneumonitis. Similarly, pneumonitis risk increased from 9% to 33% for fV5 ≥ 53% and 11% to 33% for fV20 ≥ 19%. Spared functional lung volume receiving < 5 Gy was significantly different between G<2 and G2+ pneumonitis patients (671 cc vs 935 cc, p=0.04). <h3>Conclusion</h3> This work produced dosimetric values for ventilating lung associated with symptomatic pneumonitis. Predictive functional lung dose cut-offs were lower than total lung metrics; indicating planning could focus on limiting dose to functional regions. These findings provide important metrics to be used in functional lung avoidance RT planning and designing clinical trials.

A simple-to-use nomogram for predicting the risk of radiation pneumonitis in patients with thoracic segment esophageal squamous cell carcinoma

Radiation pneumonitis (RP) is one of the most severe complications of radiotherapy (RT) or concurrent chemoradiotherapy for thoracic segment esophageal squamous cell carcinoma (TSESCC) with delayed diagnose by conventional computed tomography (CT). The study aimed to develop a nomogram to predict the risk of RP early. Data was collected from 174 patients with clinicopathologically confirmed TSESCC from October 2013 to June 2020. Procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (IL-6) levels in serum were dynamically monitored during radiotherapy. Lasso analysis was used for feature screening before multivariate logistic regression analysis to reduce the multicollinearity of variables. A nomogram combined with biological factors and clinical signs for individualized risk assessment and precise prediction of RP was developed and assed the performance with respect to its calibration, discrimination. Of the 174 patients, 30 patients developed RP (grade ≥2) while 144 patients did not. After variable screening by Lasso analysis and logistics multivariate regression analysis, the predictor variables that were finally retained in the nomogram prediction model included IL-6, CRP, and radiotherapy techniques. The model displayed good discrimination with an area under the curve (AUC) of 0.898 (95% CI: 0.849-0.947), with the sensitivity and specificity of 0.967 and of 0.736, respectively. This model also shows good calibration and clinical practical value. In addition, the study provided a web-based version of the dynamic nomogram to facilitate clinical application. The study provides a nomogram model containing IL-6, CRP, RT techniques, which could be conveniently used for individualized prediction of RP in patients with TSESCC during radiotherapy or concurrent chemoradiotherapy.

Real-world experience of consolidation durvalumab after concurrent chemoradiotherapy in stage III non-small cell lung cancer.

Durvalumab consolidation is associated with improved survival following concurrent chemoradiotherapy (CCRT) in patients with stage III non-small cell lung cancer (NSCLC). Given the heterogeneity of stage III NSCLC patients, in this study we evaluated the efficacy and safety of durvalumab in the real-world setting. Unresectable stage III NSCLC patients were retrospectively studied: one cohort received CCRT, another had CCRT-durvalumab. Primary endpoints were progression-free survival (PFS) and overall survival (OS), secondary endpoints were relapse rate and safety. In CCRT-durvalumab cohort, association between blood markers with survival and pneumonitis risk were analyzed. A total of 84 patients were enrolled: 45 received CCRT, and 39 received CCRT-durvalumab. Median PFS was 17.5months for CCRT-durvalumab and 8.9months for CCRT-alone (HR 0.47, p=0.038). Median OS was not-reached for CCRT-durvalumab and 22.3months for CCRT-alone (HR 0.35, p=0.024). Both EGFR-positive and wild-type (WT) patients had numerically improved PFS with durvalumab consolidation compared to CCRT-alone, 17.5 versus 10.9months and 11.8 versus 6.63 months, respectively (interaction p-value=0.608). Grade 2+ pneumonitis was detected in 25% of patients in the durvalumab cohort. Most pneumonitis occurred at 3.5 weeks after durvalumab initiation. Baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3 and ≥5 were associated with shorter PFS with durvalumab. Week 6 platelet-lymphocyte-ratio ≥ 180 was associated with a lower risk of pneumonitis. In this real-world study, durvalumab consolidation post CCRT was associated with a statistically significant improvement in PFS and OS. Effect of durvalumab on PFS was not modified by EGFR status. Active surveillance for pneumonitis is crucial. Baseline NLR may help to predict the benefit of treatment with durvalumab.

Personalized mid-course FDG-PET based adaptive treatment planning for non-small cell lung cancer using machine learning and optimization

Objective. Traditional radiotherapy (RT) treatment planning of non-small cell lung cancer (NSCLC) relies on population-wide estimates of organ tolerance to minimize excess toxicity. The goal of this study is to develop a personalized treatment planning based on patient-specific lung radiosensitivity, by combining machine learning and optimization. Approach. Sixty-nine non-small cell lung cancer patients with baseline and mid-treatment [18]F-fluorodeoxyglucose (FDG)-PET images were retrospectively analyzed. A probabilistic Bayesian networks (BN) model was developed to predict the risk of radiation pneumonitis (RP) at three months post-RT using pre- and mid-treatment FDG information. A patient-specific dose modifying factor (DMF), as a surrogate for lung radiosensitivity, was estimated to personalize the normal tissue toxicity probability (NTCP) model. This personalized NTCP was then integrated into a NTCP-based optimization model for RT adaptation, ensuring tumor coverage and respecting patient-specific lung radiosensitivity. The methodology was employed to adapt the treatment planning of fifteen NSCLC patients. Main results. The magnitude of the BN predicted risks corresponded with the RP severity. Average predicted risk for grade 1–4 RP were 0.18, 0.42, 0.63, and 0.76, respectively (p < 0.001). The proposed model yielded an average area under the receiver-operating characteristic curve (AUROC) of 0.84, outperforming the AUROCs of LKB-NTCP (0.77), and pre-treatment BN (0.79). Average DMF for the radio-tolerant (RP grade = 1) and radiosensitive (RP grade ≥ 2) groups were 0.8 and 1.63, p < 0.01. RT personalization resulted in five dose escalation strategies (average mean tumor dose increase = 6.47 Gy, range = [2.67–17.5]), and ten dose de-escalation (average mean lung dose reduction = 2.98 Gy [0.8–5.4]), corresponding to average NTCP reduction of 15% [4–27]. Significance. Personalized FDG-PET-based mid-treatment adaptation of NSCLC RT could significantly lower the RP risk without compromising tumor control. The proposed methodology could help the design of personalized clinical trials for NSCLC patients.

Radiation and immune checkpoint inhibitor-mediated pneumonitis risk stratification in patients with locally advanced non-small cell lung cancer: role of functional lung radiomics?

BackgroundPatients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (NSCLC) experience pulmonary toxicity at higher rates than historical reports. Identifying biomarkers beyond conventional clinical factors and radiation dosimetry is especially relevant in the modern cancer immunotherapy era. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in locally advanced NSCLC.MethodsPatients with locally advanced NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while approximately half received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (size, shape, intensity, texture) were extracted on pre-treatment [99mTc]MAA SPECT/CT perfusion images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAE v4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout.ResultsThirty-nine patients were included in the study and pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69–12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59–0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65–0.88]) or shape feature classes (c-index 0.79 [0.66–0.91]) but did not reach statistical significance compared to benchmark models (p > 0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59–0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R2 = 0.84–1.00), representing surrogates rather than independent predictors of pneumonitis risk.ConclusionsIn patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor therapy for locally advanced NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Results from this novel functional lung radiomics exploratory study can inform future validation studies to refine pneumonitis risk models following combinations of radiation and immunotherapy. Our results support functional lung radiomics as surrogates of COPD for non-invasive monitoring during and after treatment. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis risk stratification in a larger patient population is warranted.

EP05.02-022 Thoracic Radiotherapy May Increase the Risk of Treatment-induced Pneumonitis after Immune Checkpoint Inhibitors: A Meta-Analysis

Thoracic radiotherapy (TRT) combined with immune checkpoint inhibitors (ICIs) has shown promising results. However, it remains unclear whether TRT would increase the risk of lung toxicity after treatment of immune checkpoint inhibitor. This study aimed to compare the risk of treatment-related pneumonitis (TRP) between patients treated with TRT combined with immunotherapy and those with ICIs or TRT alone.

Patient selection, inter-fraction plan robustness and reduction of toxicity risk with deep inspiration breath hold in intensity-modulated radiotherapy of locally advanced non-small cell lung cancer.

BackgroundState-of-the-art radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC) is performed with intensity-modulation during free breathing (FB). Previous studies have found encouraging geometric reproducibility and patient compliance of deep inspiration breath hold (DIBH) radiotherapy for LA-NSCLC patients. However, dosimetric comparisons of DIBH with FB are sparse, and DIBH is not routinely used for this patient group. The objective of this simulation study was therefore to compare DIBH and FB in a prospective cohort of LA-NSCLC patients treated with intensity-modulated radiotherapy (IMRT).MethodsFor 38 LA-NSCLC patients, 4DCTs and DIBH CTs were acquired for treatment planning and during the first and third week of radiotherapy treatment. Using automated planning, one FB and one DIBH IMRT plan were generated for each patient. FB and DIBH was compared in terms of dosimetric parameters and NTCP. The treatment plans were recalculated on the repeat CTs to evaluate robustness. Correlations between ΔNTCPs and patient characteristics that could potentially predict the benefit of DIBH were explored.ResultsDIBH reduced the median Dmean to the lungs and heart by 1.4 Gy and 1.1 Gy, respectively. This translated into reductions in NTCP for radiation pneumonitis grade ≥2 from 20.3% to 18.3%, and for 2-year mortality from 51.4% to 50.3%. The organ at risk sparing with DIBH remained significant in week 1 and week 3 of treatment, and the robustness of the target coverage was similar for FB and DIBH. While the risk of radiation pneumonitis was consistently reduced with DIBH regardless of patient characteristics, the ability to reduce the risk of 2-year mortality was evident among patients with upper and left lower lobe tumors but not right lower lobe tumors.ConclusionCompared to FB, DIBH allowed for smaller target volumes and similar target coverage. DIBH reduced the lung and heart dose, as well as the risk of radiation pneumonitis and 2-year mortality, for 92% and 74% of LA-NSCLC patients, respectively. However, the advantages varied considerably between patients, and the ability to reduce the risk of 2-year mortality was dependent on tumor location. Evaluation of repeat CTs showed similar robustness of the dose distributions with each technique.

Clinical Outcomes Following Proton and Photon Stereotactic Body Radiation Therapy for Early-Stage Lung Cancer.

Simple SummaryThe current study reports the clinical outcomes of proton and photon stereotactic body radiation therapy (SBRT) for early-stage lung cancer. Out of 202 patients who met the inclusion criteria, 34 received proton SBRT and 168 received photon SBRT. Patients at high risk of developing post-SBRT radiation pneumonitis tended to receive proton SBRT. Oncologic outcomes and toxicity profiles were comparable between treatment modalities. Proton SBRT could be considered for patients with high risk of radiation pneumonitis.We aimed to report the clinical outcomes following stereotactic body radiation therapy (SBRT) using photon or proton equipment in early-stage lung cancer. We retrospectively reviewed 202 cT1-2N0M0 lung cancer patients who underwent SBRT with 60 Gy in four consecutive fractions between 2010 and 2019 at our institution: 168 photon SBRT and 34 proton SBRT. Patients who underwent proton SBRT had relatively poor baseline lung condition compared to those who underwent photon SBRT. Clinical outcomes were comparable between treatment modalities: 5-year local control (90.8% vs. 83.6%, p = 0.602); progression-free survival (61.6% vs. 57.8%, p = 0.370); overall survival (51.7% vs. 51.9%, p = 0.475); and cause-specific survival (70.3% vs. 62.6%, p = 0.618). There was no statistically significant difference in grade ≥ 2 toxicities: radiation pneumonitis (19.6% vs. 26.4%, p = 0.371); musculoskeletal (13.7% vs. 5.9%, p = 0.264); and skin (3.6% vs. 0.0%, p = 0.604). In the binary logistic regression analysis of grade ≥3 radiation pneumonitis, poor performance status and poor baseline diffusion capacity of lung for carbon monoxide were significant. To summarize, though patients with high risk of developing lung toxicity underwent proton SBRT more frequently, the SBRT techniques resulted in comparable oncologic outcomes with similar toxicity profiles. Proton SBRT could be considered for patients at high risk of radiation pneumonitis.

Risk of pneumonitis in non-small cell lung cancer patients with preexisting interstitial lung diseases treated with immune checkpoint inhibitors: a nationwide retrospective cohort study.

Chemotherapy for non-small cell lung cancer (NSCLC) patients with preexisting interstitial lung diseases (ILDs) increases the risk of developing pneumonitis. However, the association between pneumonitis and immune checkpoint inhibitors (ICIs) and related factors remains unclear. We conducted a retrospective cohort study using a nationwide inpatient database. We included patients (aged ≥ 20years) newly diagnosed with ILD and NSCLC and who started chemotherapy (ICIs or conventional chemotherapy) between January 2016 and December 2019. The primary endpoint was the onset of pneumonitis. We estimated the cumulative incidence function of pneumonitis and compared it with patients taking ICIs and patients receiving conventional chemotherapy using Gray's test. We calculated the subdistribution hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of pneumonitis using Fine and Gray's model to adjust for sex, age, smoking status, histology of NSCLC, surgical history, and medical histories, considering death as the competing risk. We identified 1177 patients (mean age 72years, 13.8% female), of which 328 and 849 were in the ICI and conventional chemotherapy groups, respectively. There was no significant difference in the cumulative incidence function of pneumonitis between the two groups (p = 0.868). The adjusted subdistribution HR for the incidence of pneumonitis was 1.08 (95% CI: 0.74-1.57). Age (≥ 65years) (HR: 1.86, 95% CI: 1.11-3.10) and smoking history (HR: 2.04, 95% CI: 1.02-4.11) were associated with developing pneumonitis. The risk of developing pneumonitis with ICIs for NSCLC patients with preexisting ILD was similar to that with conventional chemotherapy.

External Beam Accelerated Partial Breast Irradiation in Early Breast Cancer and the Risk for Radiogenic Pneumonitis.

Simple SummaryAccelerated partial breast irradiation represents a well-established and safe treatment alternative for selected patients with early stage breast cancer after breast-conserving surgery. In a prospective trial on external beam partial breast irradiation, the risk for radiogenic pneumonitis is analyzed. After a median follow-up of 56 (1–129) months, radiogenic pneumonitis grade 2 appeared in only 1/170 (0.6%) patients. Compared to standard whole breast irradiation, the radiation doses applied to the lungs were very low. The patient with the radiogenic pneumonitis was found to have a generally increased radiation susceptibility. Using accelerated partial breast irradiation, the risk of radiogenic pneumonitis appeared quite low and may be limited to very exceptional cases associated with innate risk factors with an increased radiation susceptibility.In order to evaluate the risk for radiation-associated symptomatic pneumonitis in a prospective external beam accelerated partial breast irradiation (APBI) trial, between 2011 and 2021, 170 patients with early stage breast cancer were enclosed in the trial. Patients were eligible for study participation if they had a histologically confirmed breast cancer or an exclusive ductal carcinoma in situ (DCIS), a tumor size ≤3 cm, free safety margins ≥2 mm, no involved axillary lymph nodes, tumor bed clips, and were ≥50 years old. Patients received APBI with 38 Gy with 10 fractions in 10 consecutive working days. The trial was registered at the German Clinical Trials Registry, DRKS-ID: DRKS00004417. Median follow-up was 56 (1–129) months. Ipsilateral lung MLD, V20, and V30 were 4.3 ± 1.4 Gy, 3.0 ± 2.0%, and 1.0 ± 1.0%, respectively. Radiogenic pneumonitis grade 2 appeared in 1/170 (0.6%) patients two months after radiotherapy. Ipsilateral MLD, V20, and V30 were 6.1 Gy, 7, and 3% in this patient. Additionally, individual radiosensitivity was increased in this specific patient. Compared to WBI, APBI leads to lower lung doses. Using APBI, the risk of symptomatic radiogenic pneumonitis is very low and may be limited, with an ipsilateral V20 < 3% to very exceptional cases associated with innate risk factors with an increased radiation susceptibility.

Pulmonary adverse events following immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have rapidly become a mainstay of cancer treatment. However, immune modulation resulting from checkpoint inhibition can cause inflammation in any organ system, with pneumonitis being one of the most severe immune-related adverse events (irAEs). Here, we review the most recent literature on pulmonary adverse events following ICIs. Several systematic reviews and meta-analyses of data from trials of antiprogrammed death-1 (PD-1; nivolumab, pembrolizumab), anti-PD-ligand-1 (PD-L1; atezolizumab, avelumab, durvalumab) and anticytotoxic T lymphocyte antigen-4 (CTLA-4; ipilimumab or tremelimumab) in patients with advanced cancer have explored the relative risk and incidence of lung toxicity among different tumor types and therapeutic regimens. They have showed that the incidence of all-grade (1-4) and high-grade (3-4) pneumonitis is significantly higher in nonsmall cell lung cancer (NSCLC) compared with other tumor types. In addition, they have demonstrated that immunotherapy, especially monoimmunotherapy, has a significantly lower risk of irAEs compared to immune-chemotherapy. Treatment for lung cancer, preexisting interstitial lung disease, smoking history and male sex appear to increase the risk for ICI-related pneumonitis. Lung toxicity is an uncommon but potentially severe and even fatal complication of ICIs. Timely recognition is critically important but challenging, particularly in patients with lung cancer wherein drug toxicity can mimic disease progression or recurrence.

Genomic Profiling Reveals Novel Predictive Biomarkers for Chemo-Radiotherapy Efficacy and Thoracic Toxicity in Non-Small-Cell Lung Cancer.

Chemo-radiotherapy (CRT) remains the main treatment modality for non-small-cell lung cancer (NSCLC). However, its clinical efficacy is largely limited by individual variations in radio-sensitivity and radiotherapy-associated toxicity. There is an urgent need to identify genetic determinants that can explain patients’ likelihood to develop recurrence and radiotherapy-associated toxicity following CRT. In this study, we performed comprehensive genomic profiling, using a 474-cancer- and radiotherapy-related gene panel, on pretreatment biopsy samples from patients with unresectable stage III NSCLCs who underwent definitive CRT. Patients’ baseline clinical characteristics and genomic features, including tumor genetic, genomic and molecular pathway alterations, as well as single nucleotide polymorphisms (SNPs), were correlated with progression-free survival (PFS), overall survival (OS), and radiotherapy-associated pneumonitis and/or esophagitis development after CRT. A total of 122 patients were enrolled between 2014 and 2019, with 84 (69%) squamous cell carcinomas and 38 (31%) adenocarcinomas. Genetic analysis confirmed the association between the KEAP1-NRF2 pathway gene alterations and unfavorable survival outcome, and revealed alterations in FGFR family genes, MET, PTEN, and NOTCH2 as potential novel and independent risk factors of poor post-CRT survival. Combined analysis of such alterations led to improved stratification of the risk populations. In addition, patients with EGFR activating mutations or any oncogenic driver mutations exhibited improved OS. On the other hand, we also identified genetic markers in relation to radiotherapy-associated thoracic toxicity. SNPs in the DNA repair-associated XRCC5 (rs3835) and XRCC1 (rs25487) were associated with an increased risk of high-grade esophagitis and pneumonitis respectively. MTHFR (rs1801133) and NQO1 (rs1800566) were additional risk alleles related to higher susceptibility to pneumonitis and esophagitis overall. Moreover, through their roles in genome integrity and replicative fidelity, somatic alterations in ZNF217 and POLD1 might also serve as risk predictors of high-grade pneumonitis and esophagitis. Taken together, leveraging targeted next-generating sequencing, we identified a set of novel clinically applicable biomarkers that might enable prediction of survival outcomes and risk of radiotherapy-associated thoracic toxicities. Our findings highlight the value of pre-treatment genetic testing to better inform CRT outcomes and clinical actions in stage III unresectable NSCLCs.

A comprehensive dosimetric comparison in adjuvant radiotherapy for various regional lymph node irradiations of left-side breast cancer using volumetric modulated arc therapy

Breast cancer is the most common cancer among women worldwide. The purpose of this study was to investigate the dosimetric parameters of critical organs for various irradiation ranges in the treatment of left-side breast cancer. The irradiation planning target volume (PTV) range in this research was divided into four groups: whole breast irradiation (group 1), whole breast with SCF irradiation (group 2), whole breast with SCF and AXLN irradiation (group 3), and whole breast with SCF, AXLN and IMN irradiation (group 4). Each group included 20 patients. We analyzed the dose parameters for the various irradiation ranges in the treatment plans retrospectively. The prescription dose was 45 Gy in 25 fractions to the PTV. In terms of the left lung, the mean dose in the four groups was 7.29 ± 1.04 Gy in group 1, 8.94 ± 2.13 Gy in group 2, 10.20 ± 1.44 Gy in group 3, and 11.44 ± 1.20 Gy in group 4. The average V5Gy, V10Gy, and V20Gy values of the left lung and whole lungs for group 1 and group 2 plans, group 1 and group 3 plans, and group 1 and group 4 plans were statistically significantly different. In terms of the heart, the average dose was 2.50 ± 0.47 Gy, 2.58 ± 0.74 Gy, 3.00 ± 0.43 Gy, and 3.97 ± 1.14 Gy in the plans of groups 1 to 4, respectively. The average V5Gy of the heart was 6.90 ± 2.26 Gy in group 1, 7.75 ± 2.58 Gy in group 2, 8.43 ± 2.10 Gy in group 3, and 13.89 ± 2.88 Gy in group 4. The study demonstrated various RT irradiation areas for left-side breast cancer patients. The dosimetric results of this research showed that an extensive volume with regional nodal irradiation may have the potential to increase the risks of radiation pneumonitis and heart disease. The comprehensive dosimetric analysis performed in this study will be helpful for clinical oncologists and medical physicists in terms of clarifying treatment plans to identify the results of any planned irradiation.

Locally advanced NSCLC: a plea for sparing the ipsilateral normal lung—prospective, clinical trial with DART-bid (dose-differentiated accelerated radiation therapy, 1.8 Gy twice daily) by VMAT

BackgroundIn radiation treatment of locally advanced non-small cell lung cancer (LA-NSCLC), ‘margins’ from internal target volumes to planning target volumes in the range of 12 to 23 mm are reported, and avoiding exposure of the contralateral lung is common practice. We investigated prospectively an approach with tight margins (7 mm) and maximal sparing of the ipsilateral normal lung. Mature results for the first endpoint (pneumonitis) and further toxicities are reported.MethodsPrimary tumors were treated by VMAT with 73.8–90.0 Gy in positive correlation to tumor volumes, nodes with 61.2 Gy, a restricted volume of nodes electively with 45 Gy. Fractional doses of 1.8 Gy bid, interval 8 h. Before radiotherapy, two cycles platin-based chemotherapy were given. 12 patients finished maintenance therapy with Durvalumab. Median follow up time for all patients is 19.4 months, for patients alive 27.0 months (3.4–66.5 months).Results100 consecutive, unselected patients with LA-NSCLC in stages II through IVA were enrolled (UICC/AJCC, 8th edition). No acute grade 4/5 toxicity occurred. Pneumonitis grade 2 and 3 was observed in 12% and 2% of patients, respectively; lowering the risk of pneumonitis grade ≥ 2 in comparison to the largest study in the literature investigating pneumonitis in LA-NSCLC, is significant (p < 0.0006). Acute esophageal toxicity grade 1, 2 and 3 occurred in 12%, 57% and 3% of patients, respectively. Two patients showed late bronchial stricture/atelectasis grade 2. In two patients with lethal pulmonary haemorrhages a treatment correlation cannot be excluded. Median overall survival for all stage III patients, and for those with ‘RTOG 0617 inclusion criteria’ is 46.6 and 50.0 months, respectively.ConclusionsOverall toxicity is low. In comparison to results in the literature, maximal sparing the ipsilateral normal lung lowers the risk for pneumonitis significantly.Trial registrationEthics committee of Vorarlberg, Austria; EK-0.04-105, Registered 04/09/2017—Retrospectively registered. http://www.ethikkommission-vorarlberg.at