Radiation-induced Pneumonitis Research Articles

Abstract 7396: Development of deep neural networks that guide more individualized radiotherapy to the lung

Abstract Introduction: Radiotherapy is dependent on an expert-based model that impedes implementation of many potentially useful applications that could aid decision makers. This model is a barrier to a learning healthcare system due to noise introduced by decision-maker variation. Surmounting this barrier will require compelling clinical outcome data and highly useful and accurate information systems. We sought to develop new augmented-intelligence capabilities to better predict both high-dose lung irradiation treatment efficacy (i.e., local tumor control) and toxicity (i.e., radiation-induced pneumonitis). Methods: We curated one of the largest datasets of lung stereotactic body radiotherapy (SBRT) datasets globally (~1200 cases). We input pre-therapy lung computed tomography (CT) images using a bounding box approach that captures the gross tumor volume and adjacent normal lung into a multi-task deep neural network to generate an image fingerprint that predicts local failures after treatment. Separately, we input axial slices from CT scans of the lung into convolutional neural network (CNN) and trained using an outcome per slice method. We then aggregated intra-patient slices into a recurrent neural network (RNN) to estimate individual patient risk for pneumonitis. We validated our findings with the independent study cohort. Risk scores for local failure and pneumonitis were combined with clinical variables to assess the relative contribution of the deep learning-derived image risk scores. Results: A total of 1045 patients met our eligibility criteria. Radiation treatments in patients with high local failure risk scores failed at a significantly higher rate than in patients with low scores; 3-year cumulative incidence of local failure in the internal study cohort was 20·3% (16·0-24·9) in patients with high scores and 5·7% (95% CI 3·5-8·8) in patients with low scores (hazard ratio [HR]=3·64 [95% CI 2·19-6·05], p<0·0001). Models that included the local failure risk score and clinical variables predicted treatment failures with a concordance index (C-index) of 0·72 (95% CI 0·67-0·77), a significant improvement compared with classical radiomics (p<0·0001) or clinical variables (p<0·0001) alone. Radiation pneumonitis risk scores were highly predictive of toxicity, with an accuracy and CI of 0.78 (95% CI 0.72-0.85). A model that includes dosimetry variates (V20), improved the CI to 0.85 (95% CI 0.80-0.90). Conclusions: The image-based deep learning frameworks developed herein represent the first opportunity to use medical images to individualize radiotherapy dose and toxicity predictions. Our results signify a new roadmap for deep learning-guided predictions and treatment guidance in the image-replete and highly standardized discipline of radiation oncology. A phase 2 study assessing machine-derived dose predictions is currently enrolling patients. Citation Format: Mohamed Abazeed. Development of deep neural networks that guide more individualized radiotherapy to the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7396.

USP11 Exacerbates Radiation-Induced Pneumonitis by Activating Endothelial Cell Inflammatory Response via OTUD5-STING Signaling

PurposeRadiation induced pneumonitis (RIP) seriously limits the application of radiotherapy in the treatment of thoracic tumors, and its etiology and pathogenesis remain elusive. This study aims to elucidate the role of Ubiquitin-specific peptidase 11 (USP11) in the progression of RIP and the associated underlying mechanisms. Methods and MaterialsThe changes of cytokines and infiltrated immune cells were detected by ELISA and IHC after exposed to 20 Gy X-ray with whole thorax irradiation. USP11 expression on endothelial cell proliferation and apoptosis were analyzed by co-staining of CD31/Ki67 and CD31/Caspase-3 in vivo and the production of cytokines and ROS were confirmed by RT-PCR and flow cytometry in vitro. Comprehensive proteome and ubiquitinome were employed for USP11 substrate screening post-radiation. Results were verified by Western blot and Co-IP experiments. rAAV-lung vectors expressing OTUD5 were utilized for localized overexpression of OTUD5 in mouse pulmonary, and IHC were conducted to analyze cytokines expression. ResultsThe progression of RIP was significantly alleviated by reduced the expression of proinflammatory cytokines in both USP11 knockout (Usp11−/−) and the USP11 inhibitor mitoxantrone treated mice. Likewise, absence of USP11 resulted in decreased permeability of pulmonary vessels and neutrophils and macrophages infiltration. The proliferation rates of endothelial cells were prominently increased in the Usp11−/− lung, while the apoptosis decreased compared to the Usp11+/+ following irradiation. Conversely, USP11 overexpression increased proinflammatory cytokines and ROS production in endothelial cells post-radiation. Comprehensive proteome and ubiquitinome analyses indicated that USP11 overexpression upregulated several deubiquitinating enzymes, including USP22, USP33 and OTUD5. We clarified that USP11 deubiquitinating OTUD5 and implicate OTUD5-STING signaling pathway in the progression of inflammatory response in endothelial cells. ConclusionsUSP11 exacerbated RIP by triggering an inflammatory response in endothelial cell both in vitro and in vivo, and OTUD5-STING pathway was involved in USP11 promotes RIP. This study provided experimental support for the development of precision intervention strategies targeting USP11 to mitigate RIP.

Intensity-modulated proton and carbon-ion radiotherapy using a fixed-beam system for locally advanced lung cancer: dosimetric comparison with x-ray radiotherapy and normal tissue complication probability (NTCP) evaluation

Objective. To assess the dosimetric consequences and the normal tissue complication probability (NTCP) for the organs at risk (OARs) in intensity-modulated particle radiotherapy of proton (IMPT) and carbon-ion (IMCT) using a fixed-beam delivery system when compared with intensity-modulated photon radiotherapy (IMRT) for locally advanced small-cell lung cancer. Approach. The plans were all designed under the same total relative biological effectiveness (RBE)-weighted prescription dose, in which the planning target volume (PTV) of the internal gross target volume(IGTV) and the PTV of the clinical target volume was irradiated with 69.3 Gy (RBE) and 63 Gy (RBE), respectively, using a simultaneously integrated boosting (SIB) technique. NTCPs were estimated for heart, lung, esophagus and spinal cord by Lyman–Kutcher–Burman (LKB) and logistic models. Dose escalation was simulated under the desired NTCP values (0.05, 0.10 and 0.50) of the three radiation techniques. Main results. Under the similar target coverage, almost all OARs were significantly better spared (p < 0.05) when using the particle radiotherapy except for D1cc (the dose to 1 cm3 of the volume) of the proximal bronchial tree (p > 0.05). At least 57.6% of mean heart dose, 28.8% of mean lung dose and 19.1% of mean esophageal dose were reduced compared with IMRT. The mean NTCP of radiation-induced pneumonitis (RP) in the ipsilateral lung was 0.39 ± 0.33 (0.39 ± 0.31) in IMPT plans and 0.36 ± 0.32 (0.35 ± 0.30) in IMCT plans compared with 0.66 ± 0.30 (0.64 ± 0.28) in IMRT plans by LKB (logistic) models. The target dose could be escalated to 78.3/76.9 Gy (RBE) in IMPT/IMCT plans compared with 61.7 Gy (RBE) in IMRT plans when 0.50 of NTCP in terms of RP in the ipsilateral lung was applied. Significance. This study presents the potential of better control of the side effects and improvement of local control originating from the dosimetric advantage with the application of IMPT and IMCT with the SIB technique for locally advanced lung cancer, even with limited beam directions.

The Impact of PM2.5 on Radiation-induced Pneumonitis in Patients With Breast Cancer.

Exposure to particulate matter (PM) air pollution is known to adversely affect respiratory disease, but no study has examined its effect on radiation-induced pneumonitis (RIP) in patients with breast cancer. We conducted a retrospective review of 2,736 patients with breast cancer who received postoperative radiation therapy (RT) between 2017 and 2020 in a single institution. The distance between the PM measurement station and our institution was only 3.43 km. PM data, including PM2.5 and PM10, were retrieved from the open dataset in the official government database. Overall incidence rate of RIP was 1.74%. After adjusting for age, RT technique, regional irradiation, fractionation and boost, the average value of PM2.5 was significantly associated with a higher risk of RIP (p=0.047) when patients received ≥20 fractions of RT. Specifically, PM2.5 ≥35 (μg/m3) showed a significantly higher risk of RIP (p=0.019) in patients with ≥20 fractions of RT. This is the first study to reveal the association between PM2.5 and RIP in patients with breast cancer who received 20 fractions or more of postoperative RT. We demonstrated that high PM2.5 levels around the RT institution were associated with RIP, suggesting that reducing PM air pollution may be a modifiable risk factor.

Serum KL-6 levels predict the occurrence and severity of treatment-related interstitial lung disease in lung cancer

In this study, we aimed to investigate the feasibility of serum Krebs von den Lungen-6 (KL-6) as a potential biomarker for treatment-related ILD (TR-ILD) in lung cancer. We recruited patients with lung cancer in whom KL-6 was measured to differentiate between pneumonia and ILD (category 1), diagnose and assess the severity of suspicious ILD (category 2), or evaluate baseline levels before cancer treatment (category 3). Among 1,297 patients who underwent KL-6 testing, 422 had lung cancer, and TR-ILD was detected in 195 patients. In categories 1–2, median KL-6 level was higher in drug-induced ILD or acute exacerbation of underlying ILD than in no ILD or radiation-induced pneumonitis, and it was correlated with the severity of TR-ILD. High KL-6 level (cut-off: > 436U/mL) was an independent risk factor for severe TR-ILD, and low KL-6 level with high procalcitonin level (> 0.5 ng/mL) could exclude severe TR-ILD. Patients with severe TR-ILD had worse overall survival than those without, whereas high baseline KL-6 level was associated with worse survival, especially in patients without severe TR-ILD. Therefore, serum KL-6 may be a surrogate marker for predicting the occurrence and assessing the severity of TR-ILD at the time of suspected ILD and before lung cancer treatment.

Radiotherapy for Patients with Locally Advanced Esophageal Squamous Cell Carcinoma Receiving Neoadjuvant Immunotherapy Combined with Chemotherapy

With the success of immunotherapy in advanced esophageal cancer, neoadjuvant chemo-immunotherapy (CIT) is being increasingly used for local staged esophageal cancer, especially in the context of clinical trials, which brings similar pCR with neoadjuvant chemoradiotherapy and shows promising results. However, there is still a part of potentially operable patients can't undergo surgery after neoadjuvant chemo-immunotherapy. The follow-up treatment and prognosis of this population remain unclear. Patients pathologically diagnosed with ESCC, clinical stage T1-3N+M0 or T3-4aNanyM0(AJCC 8th), PS 0-1 were retrospectively enrolled from 1/2020 to 6/2021 in Zhejiang Cancer Hospital. All patients firstly received PD-1 inhibitors (Camrelizumab, Sintilimab or Tislelizumab) plus chemotherapy (albumin paclitaxel,260 mg/m²on day 1 plus carboplatin AUC = 5 on day 1) every 3 weeks for 2-4 cycles. For those patients who did not receive surgery, definitive radiotherapy with 50.4Gy/28F or 50Gy/25F was adopted using VMAT, concurrent with chemotherapy or alone. The concurrent chemotherapy regimens included weekly TC (paclitaxel 50 mg/m 2, d1, carboplatin AUC = 2, d1) or S1 (60mg bid d1-14,29-42). The survival outcomes and treatment toxicity were recorded and analyzed. A total of 56 eligible patients were finally identified from 558 patients who were treated in department of thoracic surgery, 31 patients showed no response to neoadjuvant CIT (6 with PD and 25 with SD), 25 patients achieved PR but did not receive surgery due to poor performance status or refuse to operation. Median age was 66(IQR 56-72) and 55(98.2%) were males. 12(19.6%) were stage II and 44(80.4%) were stage III. Among all the patients,25 (44.6%) received radiotherapy alone, and 31 (55.4%) received chemoradiotherapy after neoadjuvant CIT. The median follow-up was 11.8 months (IQR 8.6-20.1). The median PFS and OS were 16.5 months (95CI 12.9-21.4) and 18.6 months (95CI 11.2-NA), respectively. In the subgroup analysis, the median PFS for patients with PR to CIT was 20.2 moths (95CI:17.23-NA), and 12.9 moths (95CI: 0.68-20.4) for patients with SD or PD, HR was 0.45 (95CI:0.22- 0.93, P = 0.027). No significant difference was observed for patients received radiotherapy alone or chemoradiotherapy with HR = 1.36(95CI:0.69-2.71, P = 0.37). The most common AEs observed during this study were anemia (98.2%), Leukopenia (83.9%), Thrombocytopenia (53.6%). Adverse events of grade≥3 radiation-induced pneumonitis and esophagitis were 12.5% and 32.1%, especially, 6 patients (10.7%) died from esophageal fistula and 2 patients (3.6%) died from grade 5 pneumonitis. For local advanced ESCC patients after neoadjuvant CIT who did not receive surgery, definitive radiotherapy was an optional treatment strategy. However, those patients with no response to CIT also showed poor response to radiotherapy, and particular attention should be paid to treatment related toxicity, especially esophageal fistula.

Outcomes of Consolidative Thoracic Radiation within First-Line Chemoimmunotherapy in Extensive-Stage Small-Cell Lung Cancer: Results from a Single Cancer Center

Thoracic radiation (TRT) benefits local control undoubtedly and survival with some minor controversy in extensive-stage small-cell lung cancer (ES-SCLC) patients undergoing radiotherapy in the chemoradiotherapy era. However, whether TRT could further enhance the benefit of immune checkpoint inhibitors (ICIs) maintenance on outcomes in the immunotherapy era is still unclear. This study aims to investigate the role of consolidative TRT in ES-SCLC patients receiving first-line chemoimmunotherapy followed by immunotherapy maintenance. Outcomes of patients who were treated with first-line chemo-immunotherapy followed by ICIs maintenance for ES-SCLC were reviewed. Based on TRT or not, patients were allocated to TRT group or non-TRT group. Progression-free survival (PFS), overall survival (OS) and local-recurrence free survival (LRFS) were calculated by the Kaplan-Meier method and compared by log-rank test. A total of 100 patients with no progressive disease after 4 cycles of chemotherapy were retrospectively analyzed between January 2020 and December 2021 and were allocated into TRT group (n = 47) and non-TRT group (n = 53). The median follow-up time was 20.3 months. The median PFS and OS in TRT were 9.1 months and 21.8 months, versus 8.8 months (p = 0.93) and 24.3 months (p = 0.63), respectively, in non-TRT. ICIs agents consisted of Durvalumab (59.0%) and Atezolizumab (41.0%). The median dose of TRT is 50 Gy (IQR: 45 - 54), while the median interval time from chemotherapy completion to TRT was 31 days (IQR: 12 - 44.5). Only 10 (21.3%) patients terminated ICIs in the period of TRT. The rate of intrathoracic progression after the first-line therapy in TRT significantly decreased compared to that with non-TRT (20.0% versus 55.9%, p = 0.003). The median LRFS time in TRT was not reached, but significantly longer than 10.8 months in non-TRT (HR = 0.27, p < 0.01). Second-line chemotherapy significantly prolonged survival compared to that with chemo-free patients (mOS: 24.5 vs. 21.4 months, p = 0.026). The subgroup analysis showed a trend of patients with brain metastases benefit from TRT (21.8 versus 13.7 months, HR 0.61, p = 0.38) while liver metastases did not (13.3 versus 15.0 months, HR 1.80, p = 0.21). Of 47 patients with TRT, only 10.6% of patients experienced grade 3 radiation-induced pneumonitis, while no grade 4 or 5 adverse events occurred. None of patients experienced grade ≥ 3 treatment-related cardiac events. Consolidative TRT in the period of immunotherapy maintenance followed first-line chemo-immunotherapy did not prolong OS and PFS but increased LRFS in ES-SCLC.

Pentoxifylline and Vitamin E in Preventing Pneumonitis Using Stereotactic Ablative Radiotherapy in Previously Irradiated Patients

Despite radiotherapeutic advancements, patients with non-small cell lung cancer (NSCLC) experience recurrence rates from 30-40% (1) (2). For these cases, stereotactic ablative radiotherapy (SABR) is an attractive retreatment option as studies have reported upwards of 96% local control rates at 3 years follow up (3) (4). However, thoracic reirradiation poses threat for radiation-induced pneumonitis. Particularly, the rate of grade 3 pneumonitis from institutional data was 30% in patients undergoing SABR for recurrent thoracic malignancies (4). Prior studies have tried to mitigate SABR toxicities with administration of pentoxifylline (Ptx) and vitamin E (VE), which has reduced lung damage in breast cancer patients (5) (6). The addition of Ptx and VE in retreatment of NSCLC may similarly reduce radiation-induced pneumonitis. The purpose of this study is to prospectively evaluate the efficacy of Ptx and VE in reducing grade 3 pneumonitis in patients undergoing SABR with loco-regionally recurrent lung cancer or new lung primary tumors in the setting of prior thoracic radiation. We hypothesize that these patients will experience rates of grade 3 pneumonitis lower than 30% at 3, 6, and 12-months post-treatment follow up. Patients who received radiation for a prior thoracic malignancy with a diagnosis of a recurrent or new NSCLC were recruited from our institution. Ptx and VE were administered at the time of simulation, approximately 1 week prior to starting treatment and continued for 12 weeks after the completion of treatment. SABR was delivered using standard stereotactic techniques to a dose of 5000 cGy at 1000 cGy per fraction over 2 weeks. The following demographic information was collected: baseline performance status, time interval between initial radiation and retreatment radiation, central or peripheral recurrent tumor, and pre-treatment FEV1. Patients were assessed clinically and radiographically for grades of pneumonitis at 3, 6, and 12-months post treatment. Demographic and follow-up data were collected from the initial cohort of 40 patients. There were no statistically significant correlations between pretreatment characteristics and pneumonitis. 92% of participants were medication compliant. Crude rates of pneumonitis at any time point were grade 1 (23%), grade 2 (10%), and grade 3 (2%). Only one of our patients experienced grade 3 pneumonitis. The rate of grade 3 pneumonitis in our Ptx and vitamin E treated cohort was significantly less than 30% at 3-months (p = 0.001), 6-months (p = 0.001), and 12-months (p = 0.014) post-treatment. Thus, we conclude that Ptx and VE are safe interventions that may prophylactically reduce rates of grade 3 pneumonitis for patients receiving subsequent SABR for recurrent NSCLC. Additional studies should be performed to evaluate the use in of Ptx and VE in the retreatment setting.

Hybrid Immuno-RT for Bulky Tumors: Standard Fractionation with Partial Tumor SBRT

Bulky tumors remain challenging to be treated. Stereotactic body radiation therapy (SBRT) is effective against radioresistant tumor cells and can induce immunogenic cell death (ICD) that leads to T-cell-mediated antitumor effects. Low-dose radiation (LDRT) can inflame the tumor microenvironment (TME) by recruiting T cells. We designed a novel radiotherapy technique (RT, ERT) whose dose distribution map resembles the "eclipse" by concurrently delivering LDRT to the whole tumor, meanwhile SBRT to only a part of the same tumor. This study examined the safety and efficacy of ERT to bulky lesions with PD-1 inhibitors in mice and patients. In mice with CT26 colon or LLC1 lung bulky tumors (400 - 500 cm3), the whole tumor was irradiated by LDRT (2 Gy x 3), meanwhile the tumor center was irradiated by SBRT (10 Gy x 3); αPD-1 was given weekly. The dependence of therapeutic effects on CD8+ T cells was determined using depleting antibodies. Frequencies of CD8+ T cells and M1 macrophages (Mφ) were determined by flow cytometry. Multiplex Immunohistochemistry (mIHC) was applied to analyze the number and the location of CD8+ T cells and their subpopulations, as well as the phospho-eIF2α level (the ICD marker) of tumor cells in TME. Patients with advanced lung or liver bulky tumors who failed standard treatment or with oncologic emergencies were treated. Kaplan-Meier method was applied to estimate patients' progression-free survival (PFS) and overall survival (OS). ERT/αPD-1 is superior to SBRT/αPD-1 or LDRT/αPD-1 in controlling bulky tumors in both mouse models in a CD8+ T-cell dependent manner. In the CT26 model, ERT/αPD-1 resulted in complete tumor regression in 3/11 mice and induced more CD8+ T cells and M1 Mφ in TME compared to other groups. mIHC analysis showed that ERT/αPD-1 induced higher bulk, stem-like (TCF1+ TIM3- PD-1+), and more differentiated (TCF1- TIM3+ PD-1+) CD8+ T cells infiltration into the tumor center and periphery compared to other groups. Compared to untreated or LDRT-treated tumor centers, tumor centers irradiated with ERT or SBRT showed elevated phospho-eIF2α accompanied by higher dendritic cell infiltration. In total, 39 advanced cancer patients were treated with ERT/αPD-1 or plus chemotherapy. Radiation-induced pneumonitis occurred in 1 of 26 patients receiving thoracic ERT. There were two cases of grade III toxicity associated with PD-1 inhibitors. No toxicity above grade III was observed. The objective response rate was 38.5%. The median PFS was 5.6 months and median OS was not reached at a median follow-up of 11.7 months. ERT/αPD-1 showed superior efficacy in controlling bulky tumor in two mouse models. The hybrid immuno-RT (ERT) combing PD-1 inhibitors was safe and effective in patients with bulky tumors. Further clinical trials in combination with bioimaging to identify the optimal SBRT target region for the bulky tumor are warranted.

Most Appropriate Radiation Therapy Techniques for The Breast Cancer Treatment: Dosimetric Analysis of Three Different Radiation Therapy Methods

Background: Radiation-induced cardiac events and pneumonitis are the major late radiotherapy side effects. Methods: We explored the differences in dose distribution between 3D CRT, IMRT and VMAT in 125 women with unilateral breast cancer. The various dose distribution to the tumor and OARs were studied for left and right sided irradiation. Results: Upon using 3D CRT breasts with lymph nodes, we observed a significant dose increase in the ipsilateral lung. Having irradiated only the right breast, there was a negligible Dmean difference to the adjacent lung between three methods, likewise for the myocardium in left breast cases. For right-sided cases 3D CRT showed the lowest doses in myocardium. Conclusion: Radiation oncologists should consider VMAT if conditions do not allow devising three plans with different methods. This in turn will reduce cardio and pneumotoxicity of left breast cancer treatment. In the treatment of right breast cancer, physicians should focus on 3D CRT.

Role of consolidative thoracic radiation in extensive-stage small-cell lung cancer with first-line chemoimmunotherapy: a retrospective study from a single cancer center

ObjectiveTo investigate the role of consolidative thoracic radiation (TRT) in extensive-stage small-cell lung cancer (ES-SCLC) receiving first-line chemo-immunotherapy followed by immunotherapy maintenance.Patients and methodsOutcomes of patients without disease progression after first-line chemotherapy were retrospectively reviewed (January 2020 to December 2021). Based on TRT or not, patients were allocated to TRT group or non-TRT group. Progression-free survival (PFS), overall survival (OS) and local-recurrence free survival (LRFS) were calculated by the Kaplan–Meier method and compared by log-rank test.ResultsOf 100 patients, 47 received TRT and 53 non-TRT. The median follow-up was 20.3 months. The median PFS and OS in TRT were 9.1 months and 21.8 months, versus 8.8 months (p = 0.93) and 24.3 months (p = 0.63), respectively, in non-TRT. The median LRFS time in TRT was not reached, but significantly longer than 10.8 months in non-TRT (HR = 0.27, p < 0.01). Second-line chemotherapy significantly prolonged survival compared to that with chemo-free patients (mOS: 24.5 vs. 21.4 months, p = 0.026). The subgroup analysis showed a trend of patients with brain metastases benefit from TRT (21.8 versus 13.7 months, HR 0.61, p = 0.38) while liver metastases did not. Of 47 patients with TRT, only 10.6% of patients experienced grade 3 radiation-induced pneumonitis, while no grade 4 or 5 adverse events occurred.ConclusionConsolidative TRT in the period of immunotherapy maintenance followed first-line chemo-immunotherapy did not prolong OS and PFS but associated with improved LRFS in ES-SCLC.

CBCT-guided adaptive radiotherapy using self-supervised sequential domain adaptation with uncertainty estimation.

Adaptive radiotherapy (ART) is an advanced technology in modern cancer treatment that incorporates progressive changes in patient anatomy into active plan/dose adaption during the fractionated treatment. However, the clinical application relies on the accurate segmentation of cancer tumors on low-quality on-board images, which has posed challenges for both manual delineation and deep learning-based models. In this paper, we propose a novel sequence transduction deep neural network with an attention mechanism to learn the shrinkage of the cancer tumor based on patients' weekly cone-beam computed tomography (CBCT). We design a self-supervised domain adaption (SDA) method to learn and adapt the rich textural and spatial features from pre-treatment high-quality computed tomography (CT) to CBCT modality in order to address the poor image quality and lack of labels. We also provide uncertainty estimation for sequential segmentation, which aids not only in the risk management of treatment planning but also in the calibration and reliability of the model. Our experimental results based on a clinical non-small cell lung cancer (NSCLC) dataset with sixteen patients and ninety-six longitudinal CBCTs show that our model correctly learns weekly deformation of the tumor over time with an average dice score of 0.92 on the immediate next step, and is able to predict multiple steps (up to 5 weeks) for future patient treatments with an average dice score reduction of 0.05. By incorporating the tumor shrinkage predictions into a weekly re-planning strategy, our proposed method demonstrates a significant decrease in the risk of radiation-induced pneumonitis up to 35% while maintaining the high tumor control probability.

Study of radiation-induced pneumonitis after arc and static irradiation in lungs of rats

The clinical application of the results of the experimental radiotherapy on animals is currently not widely used. The research of radiation injuries after irradiation target in rat lungs using the image-guided platform SmART+ (Precision, North Branford, Conn., USA) is a pilot study for the establishment of an animal model of radiation-induced pulmonary toxicity.Aim: To define the typical doses and target volumes in rat lung to o serve radiation pneumonitis.Material and methods. Four groups of Wistar and Wag rats, distinguishing by age (10–16,5 months) and weight (350-850 g.), were studied. Dosimetric treatment plans were calculated prior to irradiation, using arc or static methods, doses (10–30 Gy), target lung volumes (0,045–1,24 cm3), localization (right or left, top or bottom). Dosimetric planning provides optimal radiation exposure to the target and controls organ at risk doses. Computer tomography (CT) scans were performed for 16 weeks to observe radiation pneumonitisResults. To obtain the rat lung density in Hounsfield units (HU), healthy animals were scanned, CT images were processed, and the mean and standard deviation were calculated. Lung density values of rats (control values) are 519.6 ± 46.2 (HU). Comparison of experimental data on irradiated animals and control values was carried out. As a result, the relationship of the target volume, the delivered dose and the survival rate of animals after irradiation was established. It was shown that the “mean value of lung density” could be used for quantitative analysis of lung injuries after irradiation.Conclusion. Typical doses and target volumes in rat lungs to observe radiation pneumonitis were obtained. Decreasing aeration of lung tissue was derived at delivered dose 16 Gy and irradiated target volume in lung at least 0.5 cm3 (8%).

A retrospective study of adjuvant proton radiotherapy for breast cancer after lumpectomy: a comparison of conventional-dose and hypofractionated dose

PurposeThis study aimed to compare the adverse reactions of conventional-dose and hypofractionated dose of proton therapy for breast cancer.Materials and methodsBreast cancer patients treated with proton radiotherapy in conventional-dose or hypofractionated dose were studied retrospectively.ResultFrom January 2017 to December 2019, our center treated 50 patients following lumpectomy with proton radiotherapy. According to the AJCC 8th Edition standard, there were stage I in 26 patients, stage II in 22 patients, and stage III in 2 patients. A total of 14 patients received intensity-modulated proton therapy at a dose of 50 Gy in 25 fractions, followed by a 10 Gy 4 fractionated boost to the lumpectomy cavity, while 36 received 40.05 Gy in 15 fractions, simultaneous integrated boost (SIB) 48 Gy to the lumpectomy cavity. Median follow-up time for 40.05 Gy group was 35.6 months (15–43 months). Median follow-up time for 50 Gy group was 46.8 months (36–68 months). For acute toxicity, the grade 1 and 2 radiodermatitis in conventional-dose group were 35.7% and 57.1%, respectively. In hypofractionated dose group, the grade 1 and 2 radiodermatitis were 91.7% and 8.3%, respectively. The radiodermatitis is hypofractionneted dose better than conventional-dose significantly. Grade 1 radiation-induced esophagitis in conventional-dose group and hypofractionated dose group were 85.71% and 60%, respectively. For late toxicity, no patients developed radiation-induced pneumonitis and rib fracture in conventional-dose group. Three patients presented grade 1 pneumonitis; one patient presented graded 2 pneumonitides and two patients presented rib fracture in hypofractionated dose group. One presented hypothyroidism in hypofractionated dose group. All patients were satisfied with breast shape. The one- and two-year OS and DFS for conventional-dose group were 100 and 100; 100 and 92.9%, respectively. The one- and two-year OS and DFS for hypofractionated dose group were 100 and 100; 100 and 100%, respectively.ConclusionProton radiation therapy can significantly reduce the normal tissue dose in breast cancer patients' hearts, lungs, and other organs. Hypofractionated proton therapy shortens the treatment course with mild radiation-related adverse effects, and has a better effect on addressing the acute adverse reactions than conventional proton radiotherapy.

Immunomodulatory role of azithromycin: Potential applications to radiation-induced lung injury.

Radiation-induced lung injury (RILI) including radiation-induced pneumonitis and radiation-induced pulmonary fibrosis is a side effect of radiotherapy for thoracic tumors. Azithromycin is a macrolide with immunomodulatory properties and anti-inflammatory effects. The immunopathology of RILI that results from irradiation is robust pro-inflammatory responses with high levels of chemokine and cytokine expression. In some patients, pulmonary interstitial fibrosis results usually due to an overactive immune response. Growing clinical studies recently proposed that the anti-inflammatory and immunomodulatory effects of azithromycin may benefit patients with acute lung injury. It has been shown potential benefits for patients with RILI in preclinical studies. Azithromycin has a variety of immunomodulatory effect to improve the process of disease, including inhibition of pro-inflammatory cytokines production participating in the regulatory function of macrophages, changes in autophagy, and inhibition of neutrophil influx. We review the published evidence of mechanisms of azithromycin, and focus on the potential effect of azithromycin on the immune response to RILI.

Metrics of dose to highly ventilated lung are predictive of radiation-induced pneumonitis in lung cancer patients

PurposeTo identify metrics of radiation dose delivered to highly ventilated lung that are predictive of radiation-induced pneumonitis. Methods and MaterialsA cohort of 90 patients with locally advanced non-small cell lung cancer treated with standard fractionated radiation therapy (RT) (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. Multiple voxel-wise population- and individual-based thresholds for defining high functioning lung were considered. Mean dose and volumes receiving dose ≥ 5–60 Gy were analyzed for both total lung-ITV (MLD,V5-V60) and highly ventilated functional lung-ITV (fMLD,fV5-fV60). The primary endpoint was symptomatic grade 2+ (G2+) pneumonitis. Receiver operator curve (ROC) analyses were used to identify predictors of pneumonitis. ResultsG2+ pneumonitis occurred in 22.2% of patients, with no differences between stage, smoking status, COPD, or chemo/immunotherapy use between G<2 and G2+ patients (P≥ 0.18). Highly ventilated lung was defined as voxels exceeding the population-wide median of 18% voxel-level expansion. All total and functional metrics were significantly different between patients with and without pneumonitis (P≤ 0.039). Optimal ROC points predicting pneumonitis from functional lung dose were fMLD ≤ 12.3 Gy, fV5 ≤ 54% and fV20 ≤ 19 %. Patients with fMLD ≤ 12.3 Gy had a 14% risk of developing G2+ pneumonitis whereas risk significantly increased to 35% for those with fMLD > 12.3 Gy (P = 0.035). ConclusionsDose to highly ventilated lung is associated with symptomatic pneumonitis and treatment planning strategies should 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.

IDO1 Activity Predicts Lung Toxicity in Patients with Unresectable Stage III NSCLC and Chemoradiotherapy.

Indoleamine 2,3-dioxygenase 1 (IDO1) acts as the key rate-limiting enzyme that converts tryptophan (Trp) to kynurenine (Kyn). Its activity was primarily induced by interferon-γ (IFN-γ), which was reported to play a role in the development of acute radiation-induced pneumonitis. In this study, we aimed to investigate the correlation between IDO1 activity and radiation-induced lung toxicity (RILT) in stage III nonsmall cell lung cancer (NSCLC) patients who were treated with chemoradiotherapy (CRT). Systemic IDO1 activity was reflected by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 stage III NSCLC patients were measured by high-performance liquid chromatography (HPLC) before the initiation of radiotherapy. Dynamic change of IDO1 activity was followed in 23 patients before, during, and after radiotherapy. We also used RNA sequencing (RNA-seq) data from the Cancer Genome Atlas Program (TCGA) database and performed gene set enrichment analysis (GSEA) to explore how IDO1 was involved in the development of RILT. 9.7% (11/113) of the whole group developed G3+ (greater than or equal to Grade 3) RILT. Preradiation IDO1 activity was significantly higher in patients who developed G3 + RILT than in nonG3 + RILT patients. (P = 0.029, AUC = 0.70). Univariate and multivariate analyses showed that high IDO1 activity was independently associated with the risk of G3 + RILT (P = 0.034). A predictive model combining both IDO1 activity and FEV1 was established for severe RILT and displayed a moderate predictive value (AUC = 0.83, P < 0.001). The incidence of G3 + RILT was 2.6% (1/38) in patients with an IDO activity ≤0.069 and FEV1 > 59.4%, and 50.0% (6/12) in those with an IDO activity >0.069 and FEV1 ≤ 59.4%. Of 23 patients with dynamic tracking, the IDO1 activity of postradiation was significantly lower than midradiation (P = 0.021), though no significant differences among the three time points were observed (P = 0.070). Bioinformatic analysis using RNA-seq data from 1014 NSCLC patients revealed that IDO mainly functioned in the inflammatory response instead of the late fibrosis process in NSCLC patients. High baseline IDO1 activity combined with unfavorable baseline FEV1 was predictive of severe RILT in unresectable stage III NSCLC patients. IDO1 might play a role in the acute inflammatory response. Finding effective interventions to alleviate RILT using IDO inhibitors is warranted in the future.

Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD): An observational and exploratory case series of non-asian patients

Interstitial lung disease (ILD) can coexist with early-stage lung cancer (LC) and may compromise surgery and worsen patients’ outcomes. Stereotactic body radiation therapy (SBRT) is the gold standard treatment for medically inoperable early-stage lung cancer, but radiation therapy is contra-indicated for patients with ILD because of the higher risk of severe radiation-induced pneumonitis. SBRT may spare healthy lung tissue, but data are scarce in this rare population. Our exploratory case series aimed to retrospectively identify patients treated with SBRT in this setting: 19 patients were diagnosed with early-stage LC-ILD over the past 6 years and 9 received SBRT. Most of them were smokers with a median age of 71, 4 had no pathological documentation. After SBRT, 5 patients had grade I-II respiratory adverse events (AEs), but none had treatment-related grade III-IV respiratory AEs. Two patients died within 6 months of SBRT, and for both, death was related to metastatic relapse. In this case series, the radiological evolution of ILD before radiotherapy and the evolution of the radiotherapy scar on CT-Scan were also explored with different evolutionary models. This exploratory study shows available data that could be studied in a larger retrospective cohort to identify risk factors for SBRT in the LC-ILD population. The use of dosimetric data as a risk factor for SBRT should be done with cautiousness due to heterogeneous and complex dose delivery and different fractionation schedule.

The evaluation of DLCO changes in patients with relatively higher lung shunt fractions receiving TARE.

Transarterial radioembolization (TARE) with Yttrium-90 (90Y) labeled microspheres is an effective locoregional treatment option for patients with primary and metastatic liver cancer. However, TARE is also associated with radiation-induced lung injury due to hepatopulmonary shunting. If a large proportion of the injected radionuclide microspheres (more than 15%) is shunted, a rare but lethal complication may develop: radiation-induced pneumonitis (RP). Diffusion capacity of the lungs for carbon monoxide (DLCO) is a valuable test to assess lung function and a decrease in DLCO may indicate an impairment in gas exchange caused by the lung injury. Some previous researches have been reported the most consistent changes in pulmonary function tests after external beam radiotherapy are recorded with DLCO. This study aimed to examine the changes in DLCO after TARE with glass microspheres in newly treated and retreated patients with relatively higher lung shunt fractions. We prospectively analyzed forty consecutive patients with liver malignancies who underwent lobar or superselective TARE with 90Y glass microspheres. DLCO tests were performed at baseline and on days 15, 30, and 60 after the treatment. All patients were followed up clinically and radiologically for the development of RP. A statistically significant decrease was found in the DLCO after the first treatment (81.4 ± 13.66 vs. 75.25 ± 13.22,p = 0.003). The frequency of the patients with impaired DLCO at baseline was significantly increased after the first treatment (37.5 vs 57.5% p < 0.05). In the retreated group (n = 8), neither the DLCO (71.5 ± 10.82 vs. 67.50 ± 11.24,p = 0.115) nor the frequency of patients with impaired DLCO (25 vs 25%, p = 1) did not significantly change. Also, the change in DLCO values did not significantly correlate with lung shunt fraction, administered radiation dose, and absorbed lung dose after the first and second treatments (p > 0.05 for all). None of the patients developed RP. Our study showed that a significant reduction in DLCO after TARE may occur in patients with relatively higher lung shunt fractions. Further studies with larger sample sizes are needed to better investigate the changes in DLCO in patients with high lung shunt fractions.

CT radiomics-based long-term survival prediction for locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy using features from tumor and tumor organismal environment

BackgroundDefinitive concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced non-small cell lung cancer (LANSCLC) patients, but the treatment response and survival outcomes varied among these patients. We aimed to identify pretreatment computed tomography-based radiomics features extracted from tumor and tumor organismal environment (TOE) for long-term survival prediction in these patients treated with CCRT.MethodsA total of 298 eligible patients were randomly assigned into the training cohort and validation cohort with a ratio 2:1. An integrated feature selection and model training approach using support vector machine combined with genetic algorithm was performed to predict 3-year overall survival (OS). Patients were stratified into the high-risk and low-risk group based on the predicted survival status. Pulmonary function test and blood gas analysis indicators were associated with radiomic features. Dynamic changes of peripheral blood lymphocytes counts before and after CCRT had been documented.ResultsNine features including 5 tumor-related features and 4 pulmonary features were selected in the predictive model. The areas under the receiver operating characteristic curve for the training and validation cohort were 0.965 and 0.869, and were reduced by 0.179 and 0.223 when all pulmonary features were excluded. Based on radiomics-derived stratification, the low-risk group yielded better 3-year OS (68.4% vs. 3.3%, p < 0.001) than the high-risk group. Patients in the low-risk group had better baseline FEV1/FVC% (96.3% vs. 85.9%, p = 0.046), less Grade ≥ 3 lymphopenia during CCRT (63.2% vs. 83.3%, p = 0.031), better recovery of lymphopenia from CCRT (71.4% vs. 27.8%, p < 0.001), lower incidence of Grade ≥ 2 radiation-induced pneumonitis (31.6% vs. 53.3%, p = 0.040), superior tumor remission (84.2% vs. 66.7%, p = 0.003).ConclusionPretreatment radiomics features from tumor and TOE could boost the long-term survival forecast accuracy in LANSCLC patients, and the predictive results could be utilized as an effective indicator for survival risk stratification. Low-risk patients might benefit more from radical CCRT and further adjuvant immunotherapy.Trial registration:retrospectively registered.