Occurrence Of Radiation Pneumonitis Research Articles

A Prospective Study of Differences in the Incidence of Radiation Pneumonitis in Elderly Patients between Volumetric Arc Modulated Therapy and Step-and-Shoot Intensity-Modulated Radiation Therapy

<h3>Purpose/Objective(s)</h3> Studies have shown that the incidence of radiation pneumonitis in elderly patients with thoracic tumor radiotherapy is high, and there is a significant correlation with smoking, pulmonary dysfunction, combined chemotherapy, radiation dose and radiation site. VMAT is considered a large-scale low-dose radiation therapy modality, while Step and Shot's IMRT is a small-scale low-dose radiation therapy modality. To test whether these two radiotherapy modalities have different incidences of radiation pneumonitis in elderly lung cancer patients, we conducted this prospective randomized controlled study. <h3>Materials/Methods</h3> A total of 50 elderly patients with non-small cell lung cancer (NSCLC) diagnosed from January 2019 to January 2020 were included and randomly divided into the VMAT group and the IMRT group according to the ratio of 1:1. We collected all irradiated lung volumes from 5 to 75 Gy at the interval of 5 Gy. The occurrence of radiation pneumonitis within six months after treatment was followed up. Fisher's exact test was used to analyze the incidence of radiation pneumonitis between the two groups. In addition, linear regression was used to analyze the fitting situation of radiation pneumonitis in the two groups with an interval of 5 Gy. <h3>Results</h3> The average age was 69 yrs, lung volume was 3310±837 ml, radiation dose was 68.8±8.3 Gy. The I to V levels of radiation pneumonitis were 12, 10, 2, 1, 0 in VMAT and 10, 12, 3, 0,0 in IMRT, respectively, P=0.610 with Fisher`s exact test. Judging from the coefficient of determination (R2) of the fitted model, no matter which grouping, the dose and the inflammatory ratio were linearly correlated and negatively correlated. From the distribution of the scatter plot, the fitting degree of IMRT is higher, and the scatter points are more concentrated on both sides of the curve, while VMAT is more diffuse. The IMRT fitting model is Y=42.19-3.14x, and the VMAT fitting model is Y=36.48-2.91x. The β coefficient (3.14) of the former is greater than that of the latter (2.91), indicating that with the increase of radiation dose, The inflammatory ratio decreased more rapidly. <h3>Conclusion</h3> In this small prospective pilot experiment, we did not directly find a difference in the incidence of radiation pneumonitis between the two radiation therapy modalities. However, in further analysis of the dose distribution in the lungs, we found that the trend of pneumonia incidences in the IMRT group was lower than that in the VMAT group as the dose increased. This study warrants further conduct in elderly patients to demonstrate which radiotherapy modality is more appropriate.

Research Progress on Radiotherapy Combined with Immunotherapy for Associated Pneumonitis During Treatment of Non-Small Cell Lung Cancer.

Radiation pneumonitis is a common and serious complication of radiotherapy for thoracic tumours. Although radiotherapy technology is constantly improving, the incidence of radiation pneumonitis is still not low, and severe cases can be life-threatening. Once radiation pneumonitis develops into radiation fibrosis (RF), it will have irreversible consequences, so it is particularly important to prevent the occurrence and development of radiation pneumonitis. Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumour types, providing unprecedented survival in some patients, especially for the treatment of non-small cell lung cancer (NSCLC). However, in addition to its remarkable curative effect, ICls may cause immune-related adverse events. The incidence of checkpoint inhibitor pneumonitis (CIP) is 3% to 5%, and its mortality rate is 10% to 17%. In addition, the incidence of CIP in NSCLC is higher than in other tumour types, reaching 7%–13%. With the increasing use of immune checkpoint inhibitors (ICls) and thoracic radiotherapy in the treatment of patients with NSCLC, ICIs may induce delayed radiation pneumonitis in patients previously treated with radiation therapy, or radiation activation of the systemic immune system increases the toxicity of adverse reactions, which may lead to increased pulmonary toxicity and the incidence of pneumonitis. In this paper, the data about the occurrence of radiation pneumonitis, immune pneumonitis, and combined treatment and the latest related research results will be reviewed.

Lung Dose Measured on Postradioembolization 90Y PET/CT and Incidence of Radiation Pneumonitis.

Radiation pneumonitis is a rare but possibly fatal side effect of 90Y radioembolization. It may occur 1-6 mo after therapy, if a significant part of the 90Y microspheres shunts to the lungs. In current clinical practice, a predicted lung dose greater than 30 Gy is considered a criterion to exclude patients from treatment. However, contrasting findings regarding the occurrence of radiation pneumonitis and lung dose were previously reported in the literature. In this study, the relationship between the lung dose and the eventual occurrence of radiation pneumonitis after 90Y radioembolization was investigated. Methods: We retrospectively analyzed 317 90Y liver radioembolization procedures performed during an 8-y period (February 2012 to September 2020). We calculated the predicted lung mean dose (LMD) using 99mTc-MAA planar scintigraphy (LMDMAA) acquired during the planning phase and left LMD (LMDY-90) using the 90Y PET/CT acquired after the treatment. For the lung dose computation, we used the left lung as the representative lung volume, to compensate for scatter from the liver moving in the craniocaudal direction because of breathing and mainly affecting the right lung. Results: In total, 272 patients underwent 90Y procedures, of which 63% were performed with glass microspheres and 37% with resin microspheres. The median injected activity was 1,974 MBq (range, 242-9,538 MBq). The median LMDMAA was 3.5 Gy (range, 0.2-89.0 Gy). For 14 procedures, LMDMAA was more than 30 Gy. Median LMDY-90 was 1 Gy (range, 0.0-22.1 Gy). No patients had an LMDY-90 of more than 30 Gy. Of the 3 patients with an LMDY-90 of more than 12 Gy, 2 patients (one with an LMDY-90 of 22.1 Gy and an LMDMAA of 89 Gy; the other with an LMDY-90 of 17.7 Gy and an LMDMAA of 34.1 Gy) developed radiation pneumonitis and consequently died. The third patient, with an LMDY-90 of 18.4 Gy (LMDMAA, 29.1 Gy), died 2 mo after treatment, before the imaging evaluation, because of progressive disease. Conclusion: The occurrence of radiation pneumonitis as a consequence of a lung shunt after 90Y radioembolization is rare (<1%). No radiation pneumonitis developed in patients with a measured LMDY-90 lower than 12 Gy.

Prediction of Radiation Pneumonitis Using Genome-Scale Flux Analysis of RNA-Seq Derived From Peripheral Blood

Purpose: Radiation pneumonitis (RP) frequently occurs during a treatment course of chest radiotherapy, which significantly reduces the clinical outcome and efficacy of radiotherapy. The ability to easily predict RP before radiotherapy would allow this disease to be avoided.Methods and Materials: This study recruited 48 lung cancer patients requiring chest radiotherapy. For each participant, RNA sequencing (RNA-Seq) was performed on a peripheral blood sample before radiotherapy. The RNA-Seq data was then integrated into a genome-scale flux analysis to develop an RP scoring system for predicting the probability of occurrence of RP. Meanwhile, the clinical information and radiation dosimetric parameters of this cohort were collected for analysis of any statistical associations between these parameters and RP. A non-parametric rank sum test showed no significant difference between the predicted results from the RP score system and the clinically observed occurrence of RP in this cohort.Results: The results of the univariant analysis suggested that the tumor stage, exposure dose, and bilateral lung dose of V5 and V20 were significantly associated with the occurrence of RP. The results of the multivariant analysis suggested that the exposure doses of V5 and V20 were independent risk factors associated with RP and a level of RP ≥ 2, respectively. Thus, our results indicate that our RP scoring system could be applied to accurately predict the risk of RP before radiotherapy because the scores were highly consistent with the clinically observed occurrence of RP.Conclusion: Compared with the standard statistical methods, this genome-scale flux-based scoring system is more accurate, straightforward, and economical, and could therefore be of great significance when making clinical decisions for chest radiotherapy.

Bleomycin-induced pulmonary toxicity in Hodgkin`s lymphoma patients

Bleomycin used as part of many chemo-therapeutic programs for treating Hodgkin lymphoma is associated with pulmonary toxicity. Development of complications after mediastinal radiotherapy is also well-known. However, the synergistic effect of the combination of radiotherapy and bleomycin is considered in the literature much less frequently and mainly when using the total focal doses (SOD) of 36 – 40 Gy. Since 1998 the chemo-radiotherapeutic regimens applied to the treatment of Hodgkin lymphoma in the MRRC (Obninsk) has involved subradical TTD of 20 – 30 Gy. The goal of the study is to evaluate pulmonary toxicity in Hodgkin lymphoma patients treated with chemo-radiotherapy involving ABVD and mediastinal treatment with TTD of 20 – 30 Gy.Methods. A series of 142 Hodgkin lymphoma patients received ABVD and mediastinal radiotherapy at the TTD 20 – 30 Gy. Conventional film and digital chest X-rays, linear and digital tomograms taken at different stages of treatment and follow up were analysed.Results. Changes in lungs in the form of a pathologic pulmonary pattern (interstitial pneumonitis) were seen in 39 (27.5%) of 142 patients. In 10 (25.6%) of 39 patients focal or confluent pneumonitis infiltration were found, that was 7% of the whole study group. Clinical evidence of bleomycin-induced pneumonitis was found in 6 (15.4%) of 39 patients. With follow-up terms up to 60 months fibrotic changes in lungs were absent. The occurrence of radiation pneumonitis was 17.6%, radiation fibrosis – 35.9%. Fibrotic changes were mainly grade 1 (94.1%). In HL patients with bleomycin-induced pneumonitis the occurrence of radiation pneumonitis was 43.6% (17 of 39 patients), radiation fibrosis – 58.9% (23 of 39 patients) while the corresponding figures for patients who did not have bleomycin-induced pneumonitis were 8.7% (9 of 103 patients) and 27.2% (28 of 103 patients), respectively (p &lt; 0.001).Conclusion. A statistically significant increase in occurrence of radiation pneumonitis and radiation fibrosis was defined in HL patients who suffered bleomycin-induced pneumonitis.

Impact of genetic variant of HIPK2 on the risk of severe radiation pneumonitis in lung cancer patients treated with radiation therapy

BackgroundHomeodomain-interacting protein kinase 2 (HIPK2) has increasingly drawn attention as recent researches demonstrated its unique role in the regulation of multiple fundamental processes such as apoptosis, proliferation and DNA damage repair. Most importantly, HIPK2 was shown to play regulatory role in inflammation and influence the phenotype and activity of fibroblasts. In this study, we aimed to evaluate the impact of HIPK2 gene variant on risk of radiation pneumonitis for patients with pulmonary malignancies.Methods169 lung cancer patients with radiotherapy were included in our prospective study and genotyped by Sanger Sequence method. Multivariable Cox hazard analysis and multiple testing were applied to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of all factors possibly related to the risk of radiation pneumonitis (RP).ResultsPatients with Mean Lung Dose (MLD) ≥ 15Gy, Lung V20 ≥ 24% had higher risk of RP ≥ grade 2 compared with those counterparts (HR = 1.888, 95% CI: 1.186–3.004, P = 0.007; HR = 2.126, 95% CI: 1.338–3.378, P = 0.001, respectively). Importantly, CC genotype of HIPK2: rs2030712 were strongly related to an increased occurrence of RP ≥ grade 2 (HR = 2.146, 95% CI: 1.215–3.791, P = 0.009).ConclusionHIPK2: rs2030712 was found to be significantly related to RP of grade ≥ 2 in our cohort, and may thus be one of the important predictors of severe RP before radiotherapy, if further validated in larger population.Trial registrationOur study was prospective and observational. The research was registered in ClinicalTrials.gov database as NCT02490319.

Artificial Neural Network-Based Variable Importance Analysis of Prognostic Factors Related to Radiation Pneumonitis in Patients with Lung Cancer: Preliminary Study

Radiation pneumonitis (RP) is a major radiation-induced lung injury in patients with lung cancer. When an extremely high risk of severe RP is predicted, it is a critical issue that severely affects radiation dose and treatment planning. It is essential to assess which prognostic factor affects the occurrence of RP before initiating radiation treatment. In this study, we aimed to identify the variable importance (VI) of prognostic factors related to RP by using an artificial neural network (ANN) containing complex association between several prognostic factors. We reviewed 110 cases in patients with lung cancer who received radiation therapy (RT) from August 2000 to December 2018. The multi-layer perceptron algorithm, which is a back-propagation ANN algorithm, was implemented by SPSS Modeler (verl3.1, IBM SPSS Inc., Chicago, IL). The fifteen input variables were set, and the target variable was the occurrence of RP. The VI, which indicates the effect of each prognostic factor on the occurrence of RP, was analyzed by the variance-based method. To evaluate the VI of the ANN, we qualitatively compared the VI of the ANN with the odds ratios (OR) obtained from previously published literature. Patients who had an RP grade >2 comprised 13.6%. The accuracy of the ANN model was 76.92% and the and the area under the curve (AUC) was 0.774. From the results of the VI from the ANN, mean lung dose (MLD) had the highest VI among the prognostic factors at 15.96%. The OR of interstitial lung disease (ILD) was the highest at 25.70. While the VI of the ANN includes complex associations of the prognostic factors, ORs include independent associations between exposure and outcome. This preliminary study is meaningful as it proposes a method to quantify the VI of prognostic factors related to patient outcome using even simple ML algorithm. By further acquiring the more refined big data, optimizing the ML model, and performing clinical validation, the accurate VI can be adopted for personalized RT planning.

Predicting dosimetric indices in IMRT planning for lung cancer patients

Purpose: For lung cancer patients treated with intensity modulated radiation therapy (IMRT) technique, several dosimetric indices of lungs such as the mean lung dose, V30, V20 and V10 have drawn high attention, given their close correlations with the occurrence of radiation pneumonitis. In this study, we developed a method to predict the indices V30, V20 and V10 before treatment planning. Methods and Materials: The work in this study utilises anatomical information to predict dosimetric indices of lungs for IMRT plans. 15 shells surrounding the PTV were created and each shell comprised voxels whose distances to PTV surface were within a certain distance. The overlap regions of the lungs and the 15 shells were determined. A linear predicting function is employed to map volumes of these regions to dosimetric indices, where parameters were fitted using previous IMRT plans from a training database consisting of 43 cases. The effectiveness of the predicting function was validated using another 14 plans. Results: Dosimetric indices of the 14 patients in validation cohort were calculated using the linear predicting function. The predicted indices were compared with the indices derived from the clinically accepted treatment plans. The absolute differences between calculated V30 and the actual clinical values of 14 plans had a mean value of 1.6% and a standard deviation of 1.0%. The mean value and standard deviation for absolute differences of V20 were 1.5% and 1.0%. And for V10, these values were 3.6% and 2.6%. Conclusions: The method proposed here can predict dosimetric indices of lungs before treatment planning using geometric information of delineated PTVs and lungs. The results show that the prediction error of V30 and V20 are less than about 2.0%.

Variations of circulating endothelial progenitor cells and transforming growth factor-beta-1 (TGF-β1) during thoracic radiotherapy are predictive for radiation pneumonitis

BackgroundThe vascular endothelial cells are important targets of radiotherapy, which may be involved in the pathogenesis of radiation pneumonitis (RP). This study investigated the variations of circulating endothelial progenitor cells (EPCs) and transforming growth factor-beta-1 (TGF-β1) during three-dimensional conformal radiation therapy (3D-CRT) in patients with non–small-cell lung cancer (NSCLC) and analyzed the correlation between these variations with the occurrence of RP.Patients and methodsFrom November 2008 to November 2009, eighty-four consecutive patients receiving 3D-CRT for stage III disease were evaluated prospectively. Circulating EPCs and TGF-β1 levels were measured at baseline, every 2 weeks during, and at the end of treatment. RP was evaluated prospectively at 6 weeks after 3D-CRT.ResultsThirty-eight patients (47.5%) experienced score 1 or more of RP. The baseline levels of EPCs and TGF-β1 were analyzed, no difference was found between patients with and without RP during and after 3D-CRT. By serial measurement of TGF-β1 and EPCs levels, we found that the mean levels of EPCs in the whole population remained stable during radiotherapy, but the mean levels of TGF-β1 increased slowly during radiotherapy. TGF-β1 and EPCs levels were all significantly higher at week 2, week 4 and week 6 in patients with RP than that in patients without RP, respectively. During the period of radiation treatment, TGF-β1 levels began to increase in the first 2 weeks and became significantly higher at week 6 (P < 0.01). EPCs levels also began to increase in the first 2 weeks and reached a peak at week 4. Using an ANOVA model for repeated-measures, we found significant associations between the levels of TGF-β1 and EPCs during the course of 3D-CRT and the risk of developing RP (P < 0.01). Most of the dosimetric factors showed a significant association with RP.ConclusionEarly variations of TGF-β1 and EPCs levels during 3D-CRT are significantly associated with the risk of RP. Variations of circulating TGF-β1 and EPCs levels during 3D-CRT may serve as independent predictive factors for RP.Trial registrationTrials registration number: 20070618

Severe COPD Is Correlated With Mild Radiation Pneumonitis Following Stereotactic Body Radiotherapy

The primary cause of COPD and lung cancer is smoking. Thus, patients with COPD frequently have lung cancer that often is inoperable. Stereotactic body radiation therapy (SBRT) is anticipated to be the standard of care for inoperable early stage non-small cell lung cancer. The most critical toxicity following SBRT is radiation pneumonitis (RP). We analyzed predictive factors for RP following SBRT and investigated the degree and occurrence of RP in patients with severe COPD. We retrospectively evaluated 265 lung tumors treated with SBRT between 2005 and 2010 with a minimum follow-up of 6 months. Predictive factors for RP, including GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage and pack-years smoked, were evaluated by univariate and multivariate analyses. RP was graded according to the Common Terminology Criteria for Adverse Events version 3.0 scale. Median follow-up was 19.2 months (range, 6.0-72.0 months). RP grades of 0, 1, 2, 3, 4, and 5 occurred in 101, 102, 49, 12, 0, and one of these patients, respectively. Multivariate analysis revealed that high normal lung volume receiving ≥ 20 Gy, fewer pack-years smoked, and high total dose were significant predictive factors for RP ≥ grade 1, and high normal lung volume receiving 20 Gy, fewer pack-years smoked, and a history of lung resection were predictive for RP ≥ grade 2. RP in patients with more severe COPD was relatively milder than in patients with normal lung function and with mild COPD. Pack-year scales were significantly correlated with GOLD stage. RP following SBRT in patients with severe COPD was relatively mild. Heavy smoking was the strongest negative predictor for severe RP and was correlated with severe COPD. Further follow-up and quantitative analysis of lung function might be needed to ascertain longer tolerability to SBRT.

Analysis of related factors associated with radiation pneumonitis in patients with locally advanced non-small-cell lung cancer treated with three-dimensional conformal radiotherapy

To investigate the correlation among DVH (lung dose-volume histogram) parameters, clinical factors, and grade > or = 2 radiation pneumonitis (RP) in patients with locally advanced non-small-cell lung cancer (NSCLC) treated with three-dimensional conformal radiotherapy (3D-CRT), and the differences between patients treated with 3D-CRT alone or that combined with chemotherapy on RP. As much as 93 patients of stage III NSCLC were treated with 3D-CRT, among which 36 were treated with chemotherapy after 3D-CRT, 57 received 3D-CRT treatment alone. The radiation dose was 62.5-65 Gy (BED = 68-72.7 Gy). The morbidity of grade > or = 2 RP was 49.5%, of which grade 2 and grade 3 were 33.3 and 16.1%, respectively. The morbidity of RP in those patients treated with chemotherapy after radiotherapy was evidently higher than that of patients treated with radiotherapy alone (61.1 vs. 42.1%). According to the single factor analysis, V5-V50 and MLD of both the ipsilateral and the whole lung were all related to the occurrence of RP; comparing grade 3 with grade 2 within the same group, except V45, V50, TV20, TV30, and TMLD, other parameters also had their statistical significance (P < 0.01); comparing the non-chemotherapy-treated group with the chemotherapy-treated group, TV30 and TV35 had their statistical significance. According to logistic regression analysis; the occurrence of RP was evidently associated with the comprehensive value of DVH parameters, chemotherapy, and gender. Chemotherapy has increased the risk of RP 7.6 times. The increase of each score in the comprehensive value of DVH parameters would increase the risk of RP 22.7 times. The comprehensive values of DVH parameters, chemotherapy, and gender have independent effects on the occurrence of RP. Most of DVH parameters were associated with the occurrence of RP. The curve shape composed of multiple points in DVH parameters was more important than any single DVH parameter.

Circulating molecular markers in predicting radiation-induced lung damage

7144 Background: We hypothesized that circulating molecular markers such as transforming growth factor-beta1 (TGF-β1), interleukin-6 (IL-6), and angiotensin-converting enzyme (ACE) change early during the course of radiotherapy (RT), and that such changes precede RILD after completion of the therapy. Methods and Materials: Patients with stage I-III NSCLC treated with RT (11) or chemoRT (15) (enrolled onto two prospective clinical trials) were included in this study. Serum and platelet poor plasma were obtained prior to (Pre-RT), at 40–50 Gy (during-RT), and at the end of RT (end-RT). The plasma TGF-β1 and IL-6 and serum ACE levels were measured using molecule specific enzyme-linked immunosorbent assays. The endpoints for RILD were ≥ grade 2 radiation pneumonitis (RP) and measures of pulmonary function tests such as forced vital capacity (FVC), forced expiratory volume in the 1st second (FEV1), and diffusing capacity for carbon monoxide (DLCO). The minimal follow-up duration was 3 months. Data is presented as mean ± standard deviation; student t-test was used for significant analysis. Results: Plasma TGF-β1 and IL-6 levels changed remarkably after 40–50 Gy of RT. The mean relative TGF-β1 levels (during-RT over pre-RT) were 1.9 ± 0.9 and 0.9 ± 0.6 in patients with and without RP (p = 0.010), respectively. There were no significant associations between changes of plasma IL-6 and ACE levels and the occurrence of RP. Significant DLCO reduction was observed at 3 months after RT in almost every patient, and such reduction was significantly more remarkable in those who had radiation induced elevation in plasma IL-6 levels (34.8 ± 15.9% versus 15.6 ± 14.5%, p = 0.045). Interestingly, the pre-RT ACE level was significantly associated with changes of FEV1 (p = 0.037) and FVC (p = 0.014): improvement of 13.2 ± 12.0% and 11.0 ± 9.0% versus reduction of 7.6 ± 17.0% and 10.8 ± 17.7% for patients with high versus low levels, respectively. Conclusion: Radiation induced elevation in circulating TGF-β1 and IL-6 levels may be predictive of RILD, while serum ACE level may be associated with decreased risk of RILD. No significant financial relationships to disclose.

Predictors of radiation pneumonitis after radiotherapy in lung cancer

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