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Background and purpose: Objective assessment of delivered radiotherapy (RT) to thoracic organs requires fast and accurate deformable dose mapping. The aim of this study was to implement and evaluate an artificial intelligence (AI) deformable image registration (DIR) and organ segmentation-based AI dose mapping (AIDA) applied to the esophagus and the heart. Materials and methods: AIDA metrics were calculated for 72 locally advanced non-small cell lung cancer patients treated with concurrent chemo-RT to 60 Gy in 2 Gy fractions in an automated pipeline. The pipeline steps were: (i) automated rigid alignment and cropping of planning CT to week 1 and week 2 cone-beam CT (CBCT) field-of-views, (ii) AI segmentation on CBCTs, and (iii) AI-DIR-based dose mapping to compute dose metrics. AIDA dose metrics were compared to the planned dose and manual contour dose mapping (manual DA). Results: AIDA required ∼2 min/patient. Esophagus and heart segmentations were generated with a mean Dice similarity coefficient (DSC) of 0.80±0.15 and 0.94±0.05, a Hausdorff distance at 95th percentile (HD95) of 3.9±3.4 mm and 14.1±8.3 mm, respectively. AIDA heart dose was significantly lower than the planned heart dose (p = 0.04). Larger dose deviations (>=1Gy) were more frequently observed between AIDA and the planned dose (N = 26) than with manual DA (N = 6). Conclusions: Rapid estimation of RT dose to thoracic tissues from CBCT is feasible with AIDA. AIDA-derived metrics and segmentations were similar to manual DA, thus motivating the use of AIDA for RT applications.

Abstract Although concurrent chemoradiation (CRT) and durvalumab consolidation has become a standard treatment for stage III non-small cell lung cancer (NSCLC), clinicopathologic and genomic factors associated with its efficacy remain poorly characterized. Here, in a multi-institutional retrospective cohort study of 328 patients treated with CRT and durvalumab, we identify that very high PD-L1 tumor proportion score (TPS) expression ( ≥ 90%) and increased tumor mutational burden (TMB) are independently associated with prolonged disease control. Additionally, we identify the impact of pneumonitis and its timing on disease outcomes among patients who discontinue durvalumab: compared to patients who experienced early-onset pneumonitis (

Background: Electromagnetic transponders bronchoscopically implanted near the tumor can be used to monitor deep inspiration breath hold (DIBH) for thoracic radiation therapy (RT). The feasibility and safety of this approach require further study. Methods: We enrolled patients with primary lung cancer or lung metastases. Three transponders were implanted near the tumor, followed by simulation with DIBH, free breathing, and 4D-CT as backup. The initial gating window for treatment was ±5 mm; in a second cohort, the window was incrementally reduced to determine the smallest feasible gating window. The primary endpoint was feasibility, defined as completion of RT using transponder-guided DIBH. Patients were followed for assessment of transponder- and RT-related toxicity. Results: We enrolled 48 patients (35 with primary lung cancer and 13 with lung metastases). The median distance of transponders to tumor was 1.6 cm (IQR 0.6–2.8 cm). RT delivery ranged from 3 to 35 fractions. Transponder-guided DIBH was feasible in all but two patients (96% feasible), where it failed because the distance between the transponders and the antenna was >19 cm. Among the remaining 46 patients, 6 were treated prone to keep the transponders within 19 cm of the antenna, and 40 were treated supine. The smallest feasible gating window was identified as ±3 mm. Thirty-nine (85%) patients completed one year of follow-up. Toxicities at least possibly related to transponders or the implantation procedure were grade 2 in six patients (six incidences, cough and hemoptysis), grade 3 in three patients (five incidences, cough, dyspnea, pneumonia, and supraventricular tachycardia), and grade 4 pneumonia in one patient (occurring a few days after implantation but recovered fully and completed RT). Toxicities at least possibly related to RT were grade 2 in 18 patients (41 incidences, most commonly cough, fatigue, and pneumonitis) and grade 3 in four patients (seven incidences, most commonly pneumonia), and no patients had grade 4 or higher toxicity. Conclusions: Bronchoscopically implanted electromagnetic transponder–guided DIBH lung RT is feasible and safe, allowing for precise tumor targeting and reduced normal tissue exposure. Transponder–antenna distance was the most common challenge due to a limited antenna range, which could sometimes be circumvented by prone positioning.

There is a need to identify predictive biomarkers to guide treatment strategies in stage III non-small cell lung cancer (NSCLCs). In this multi-institutional cohort of 197 patients with stage III NSCLC treated with concurrent chemoradiation (cCRT) and durvalumab consolidation, we identify that low tumor aneuploidy is independently associated with prolonged progression-free survival (HR 0.63; p=0.03) and overall survival (HR 0.50; p=0.03). Tumors with high aneuploidy had a significantly greater incidence of distant metastasis and shorter median distant-metastasis free survival (p=0.04 and p=0.048, respectively), but aneuploidy level did not associate with local-regional outcomes. Multiplexed immunofluorescence analysis in a cohort of NSCLC found increased intratumoral CD8-positive, PD-1-positive cells, double-positive PD-1 CD8 cells, and FOXP3-positive T-cell in low aneuploid tumors. Additionally, in a cohort of 101 patients treated with cCRT alone, tumor aneuploidy did not associate with disease outcomes. These data support the need for upfront treatment intensification strategies in stage III NSCLC patients with high aneuploid tumors and suggest that tumor aneuploidy is a promising predictive biomarker.

Purpose: The use of stereotactic body radiation therapy for ultracentral lung tumors is limited by increased toxicity. We hypothesized that using published normal tissue complication probability (NTCP) and tumor control probability (TCP) models could improve the therapeutic ratio between tumor control and toxicity. A proposed model-based approach was applied to virtually replan early-stage non-small cell lung cancer (NSCLC) tumors. Methods and Materials: The analysis included 63 patients with ultracentral NSCLC tumors treated at our center between 2008 and 2017. Along with current clinical constraints, additional NTCP model-based criteria, including for grade 3+ radiation pneumonitis (RP3+) and grade 2+ esophagitis, were implemented using 4 different fractionation schemes. Scaled dose distributions resulting in the highest TCP without violating constraints were selected (optimal plan [Planopt]). Planopt predictions were compared with the observed local control and toxicities. Results: The observed 2-year local control rate was 72% (95% CI, 57%-88%) compared with 87% (range, 6%-93%) for Planopt TCP. Thirty-nine patients had Planopt with TCP > 80%, and 14 patients had Planopt TCP < 50%. The Planopt NTCPs for RP3+ were reduced by nearly half compared with patients’ observed RP3+. The RP3+ NTCP was the most frequent reason for TCP of Planopt < 80% (14/24 patients), followed by grade 2+ esophagitis NTCP (5/24 patients) due to larger tumors (>40 cc vs ≤40 cc; P = .002) or a shorter tumor to esophagus distance (≥5 cm vs

PurposeStereotactic body radiation therapy (SBRT) has become the standard of care for inoperable early-stage non-small cell lung cancer and is often used for recurrent lung cancer and pulmonary metastases. Radiation-induced lung toxicity (RILT), including radiation pneumonitis and pulmonary fibrosis, is a major concern for which it is important to understand dosimetric and clinical predictors.Methods and materialsThis study was undertaken through the American Association of Physicists in Medicine's Working Group on Biological Effects of Stereotactic Body Radiotherapy. Data from studies of lung SBRT published through the summer of 2016 that provided detailed information about RILT were analyzed.ResultsNinety-seven studies were ultimately considered. Definitions of the risk organ and complication endpoints as well as dose-volume information presented varied among studies. The risk of RILT, including radiation pneumonitis and pulmonary fibrosis, was reported to be associated with the size and location of the tumor. Patients with interstitial lung disease appear to be especially susceptible to severe RILT. A variety of dosimetric parameters were reported to be associated with RILT. There was no apparent threshold "tolerance dose-volume" level. However, most studies noted safe treatment with a rate of symptomatic RILT of

Introduction: Pulmonary toxicity is dose-limiting in stereotactic body radiation therapy (SBRT) for tumors that abut the proximal bronchial tree (PBT), esophagus, or other mediastinal structures. In this work we explored published models of pulmonary toxicity following SBRT for such ultracentral tumors in an independent cohort of patients. Methods: The PubMed database was searched for pulmonary toxicity models. Identified models were tested in a cohort of patients with ultracentral lung tumors treated between 2008 and 2017 at one large center (N = 88). This cohort included 60 % primary and 40 % metastatic tumors treated to 45 Gy in 5 fractions (fx), 50 Gy in 5 fx, 60 Gy in 8 fx, or 60 Gy in 15 fx prescribed as 100 % dose to PTV. Results: Seven published NTCP models from two studies were identified. The NTCP models utilized PBT max point dose (Dmax), D0.2 cm3, V65, V100, and V130. Within the independent cohort, the ≥ grade 3 toxicity and grade 5 toxicity rates were 18 % and 7–10 %, respectively, and the Dmax models best described pulmonary toxicity. The Dmax to 0.1 cm3 model was better calibrated and had increased steepness compared to the Dmax model. A re-planning study minimizing PBT 0.1 cm3 to below 122 Gy in EQD23 (for a 10 % ≥grade 3 pulmonary toxicity) was demonstrated to be completely feasible in 4/6 patients, and dose to PBT 0.1 cm3 was considerably lowered in all six patients. Conclusions: Pulmonary toxicity models were identified from two studies and explored within an independent ultracentral lung tumor cohort. A modified Dmax to 0.1 cm3 PBT model displayed the best performance. This model could be utilized as a starting point for rationally constructed airways constraints in ultracentral patients treated with SBRT or hypofractionation.

BackgroundSensitive and reliable biomarkers for early detection of recurrence are needed to improve post-definitive radiation risk stratification, disease management, and outcomes for patients with unresectable early-stage or locally advanced non-small cell lung cancer (NSCLC) who are treated with definitive radiation therapy (RT). This prospective, multistate single-center, cohort study investigated the association of circulating tumor DNA (ctDNA) status with recurrence in patients with unresectable stage I-III NSCLC who underwent definitive RT.MethodsA total of 70 serial plasma samples from 17 NSCLC patients were collected before, during, and after treatment. A personalized, tumor-informed ctDNA assay was used to track a set of up to 16 somatic, single nucleotide variants in the associated patient’s plasma samples.ResultsPre-treatment ctDNA detection rate was 82% (14/17) and varied based on histology and stage. ctDNA was detected in 35% (6/17) of patients at the first post-RT timepoint (median of 1.66 months following the completion of RT), all of whom subsequently developed clinical progression. At this first post-RT time point, patients with ctDNA-positivity had significantly worse progression-free survival (PFS) [hazard ratio (HR): 24.2, p=0.004], and ctDNA-positivity was the only significant prognostic factor associated with PFS (HR: 13.4, p=0.02) in a multivariate analysis. All patients who developed clinical recurrence had detectable ctDNA with an average lead time over radiographic progression of 5.4 months, and post-RT ctDNA positivity was significantly associated with poor PFS (p

PurposeFor patients receiving lung stereotactic ablative radiotherapy (SABR), evidence suggests that high peritumor density predicts an increased risk of microscopic disease (MDE) and local-regional failure, but only if there is low or heterogenous incidental dose surrounding the tumor (GTV). A data-mining method (Cox-per-radius) has been developed to investigate this dose-density interaction. We apply the method to predict local relapse (LR) and regional failure (RF) in patients with non-small cell lung cancer.Methods199 patients treated in a routine setting were collated from a single institution for training, and 76 patients from an external institution for validation. Three density metrics (mean, 90th percentile, standard deviation (SD)) were studied in 1mm annuli between 0.5cm inside and 2cm outside the GTV boundary. Dose SD and fraction of volume receiving less than 30Gy were studied in annuli 0.5-2cm outside the GTV to describe incidental MDE dosage. Heat-maps were created that correlate with changes in LR and RF rates due to the interaction between dose heterogeneity and density at each distance combination. Regions of significant improvement were studied in Cox proportional hazards models, and explored with and without re-fitting in external data. Correlations between the dose component of the interaction and common dose metrics were reported.ResultsLocal relapse occurred at a rate of 6.5% in the training cohort, and 18% in the validation cohort, which included larger and more centrally located tumors. High peritumor density in combination with high dose variability (0.5 - 1.6cm) predicts LR. No interactions predicted RF. The LR interaction improved the predictive ability compared to using clinical variables alone (optimism-adjusted C-index; 0.82 vs 0.76). Re-fitting model coefficients in external data confirmed the importance of this interaction (C-index; 0.86 vs 0.76). Dose variability in the 0.5-1.6 cm annular region strongly correlates with heterogeneity inside the target volume (SD; ρ = 0.53 training, ρ = 0.65 validation).ConclusionIn these real-world cohorts, the combination of relatively high peritumor density and high dose variability predicts increase in LR, but not RF, following lung SABR. This external validation justifies potential use of the model to increase low-dose CTV margins for high-risk patients.

BackgroundThe COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic.MethodsFor this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk-benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC.ResultsIn a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided.ConclusionThis joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic.

Abstract Background Diffuse pleural mesothelioma (DPM) is an aggressive malignancy that, despite recent treatment advances, has unacceptably poor outcomes. Therapeutic research in DPM is inhibited by a paucity of preclinical models that faithfully recapitulate the human disease. Methods We established 22 patient-derived xenografts (PDX) from 22 patients with DPM and performed multi-omic analyses to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes of these PDX models and compared features to those of the matched primary patient tumors. Targeted next-generation sequencing (NGS; MSK-IMPACT), immunohistochemistry, and histologic subtyping were performed on all available samples. RNA sequencing was performed on all available PDX samples. Clinical outcomes and treatment history were annotated for all patients. Platinum-doublet progression-free survival (PFS) was determined from the start of chemotherapy until radiographic/clinical progression and grouped into < or ≥ 6 months. Results PDX models were established from both treatment naïve and previously treated samples and were noted to closely resemble the histology, genomic landscape, and proteomic profiles of the parent tumor. After establishing the validity of the models, transcriptomic analyses demonstrated overexpression in WNT/β-catenin, hedgehog, and TGF-β signaling and a consistent suppression of immune-related signaling in PDXs derived from patients with worse clinical outcomes. Conclusions These data demonstrate that DPM PDX models closely resemble the genotype and phenotype of parental tumors, and identify pathways altered in DPM for future exploration in preclinical studies.