Severe Radiation Pneumonitis Research Articles

Symptomatic Radiation Pneumonitis in NSCLC Patients Receiving EGFR-TKIs and Concurrent Once-daily Thoracic Radiotherapy: Predicting the Value of Clinical and Dose-volume Histogram Parameters.

Background and objectivesThe incidence of symptomatic radiation pneumonitis (RP) and its relationship with dose-volume histogram (DVH) parameters in non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and concurrent once-daily thoracic radiotherapy (TRT) remain unclear. We aim to analyze the values of clinical factors and dose-volume histogram (DVH) parameters to predict the risk for symptomatic RP in these patients.MethodsBetween 2011 and 2019, we retrospectively analyzed and identified 85 patients who had received EGFR-TKIs and once-daily TRT simultaneously (EGFR-TKIs group) and 129 patients who had received concurrent chemoradiotherapy (CCRT group). The symptomatic RP was recorded according to the Common Terminology Criteria for Adverse Event (CTCAE) criteria (grade 2 or above). Statistical analyses were performed using SPSS 26.0.ResultsIn total, the incidences of symptomatic (grade≥2) and severe RP (grade≥3) were 43.5% (37/85) and 16.5% (14/85) in EGFR-TKIs group vs 27.1% (35/129) and 10.1% (13/129) in CCRT group respectively. After 1:1 ratio between EGFR-TKIs group and CCRT group was matched by propensity score matching, chi-square test suggested that the incidence of symptomatic RP in the MATCHED EGFR-TKIs group was higher than that in the matched CCRT group (χ2=4.469, P=0.035). In EGFR-TKIs group, univariate and multivariate analyses indicated that the percentage of ipsilateral lung volume receiving ≥30 Gy (ilV30) [odds ratio (OR): 1.163, 95%CI: 1.036-1.306, P=0.011] and the percentage of total lung volume receiving ≥20 Gy (tlV20) (OR: 1.171, 95%CI: 1.031-1.330, P=0.015), with chronic obstructive pulmonary disease (COPD) or not (OR: 0.158, 95%CI: 0.041-0.600, P=0.007), were independent predictors of symptomatic RP. Compared to patients with lower ilV30/tlV20 values (ilV30 and tlV20 < cut-off point values) and without COPD, patients with higher ilV30/tlV20 values (ilV30 and tlV20 > cut-off point values) and COPD had a significantly higher risk for developing symptomatic RP, with a hazard ratio (HR) of 1.350 (95%CI: 1.190-1.531, P < 0.001).ConclusionPatients receiving both EGFR-TKIs and once-daily TRT were more likely to develop symptomatic RP than patients receiving concurrent chemoradiotherapy. The ilV30, tlV20, and comorbidity of COPD may predict the risk of symptomatic RP among NSCLC patients receiving EGFR-TKIs and conventionally fractionated TRT concurrently.

Is Thoracic Radiotherapy an Absolute Contraindication for Treatment of Lung Cancer Patients With Interstitial Lung Disease? A Systematic Review

Thoracic radiotherapy decisions in patients with interstitial lung disease (ILD) are complex due to concerns about severe or even fatal radiation pneumonitis. This systematic review analysed the published evidence regarding the incidence of radiation pneumonitis and mortality after thoracic radiotherapy and investigated clinical and dosimetric predictors of radiation pneumonitis in lung cancer patients with ILD. A systematic search was carried out in PubMed, Medline, Embase and the Cochrane database for articles published between January 2000 and April 2021. Two authors independently screened eligible studies that met our predefined criteria. Studies were assessed for design and quality and a qualitative data synthesis was carried out. The search strategy resulted in 1750 articles. After two rounds of screening, 24 publications were included. The median overall incidence of grade ≥3 radiation pneumonitis was 19.7% (range 8–46%). The incidence was greater in conventional radical radiotherapy-treated patients (median 31.8%) compared with particle beam therapy- or stereotactic ablative radiotherapy-treated patients (median 12.5%). The median rate of grade 5 radiation pneumonitis was 11.9% (range 0–60%). The presence of ILD was an independent predictor of severe radiation pneumonitis. Severe radiation pneumonitis was more common in the presence of usual interstitial pneumonia (UIP) pattern or idiopathic pulmonary fibrosis (IPF) than non-UIP or non-IPF subtype. Several other clinical predictors were reported in the literature. V5, V10, V20 and mean lung dose were the most common dosimetric predictors for severe radiation pneumonitis, often with stricter dose constraints than conventionally used. Patients with lung cancer associated with ILD had a poorer overall survival compared with patients without ILD. In conclusion, patients with lung cancer associated with ILD have a poor prognosis. They are at high risk of severe and even fatal radiation pneumonitis. Careful patient selection is necessary, appropriate high-risk consenting and strict lung dose-volume constraints should be used, if these patients are to be treated with thoracic radiotherapy.

Risk factors for radiation pneumonitis after rotating gantry intensity-modulated radiation therapy for lung cancer

The risk factors for severe radiation pneumonitis (RP) in patients with lung cancer who undergo rotating gantry intensity-modulated radiation therapy (IMRT) using volumetric modulated arc therapy (VMAT) or helical tomotherapy (HT) are poorly understood. Fifty-two patients who received rotating gantry IMRT for locally advanced lung cancer were included in this retrospective study. In total, 31 and 21 patients received VMAT and HT, respectively. The median follow-up duration was 14 months (range, 5.2–33.6). Twenty (38%) and eight (15%) patients developed grade ≥ 2 and ≥ 3 RP, respectively. In multivariate analysis, lung V5 ≥ 40% was associated with grade ≥ 2 RP (P = 0.02), and past medical history of pneumonectomy and total lung volume ≤ 3260 cc were independently associated with grade ≥ 3 RP (P = 0.02 and P = 0.03, respectively). Rotating gantry IMRT was feasible and safe in patients with lung cancer undergoing definitive radiotherapy. Reducing lung V5 may decrease the risk of symptomatic RP, and care should be taken to avoid severe RP after radiotherapy in patients with a past medical history of pneumonectomy and small total lung volume.

Computed Tomography-Based Delta-Radiomics Analysis for Discriminating Radiation Pneumonitis in Patients With Esophageal Cancer After Radiation Therapy.

Our purpose was to construct a computed tomography (CT)-based delta-radiomics nomogram and corresponding risk classification system for individualized and accurate estimation of severe acute radiation pneumonitis (SARP) in patients with esophageal cancer (EC) after radiation therapy. Four hundred patients with EC were enrolled from 2 independent institutions and were divided into the training (n=200) and validation (n=200) cohorts. Eight hundred fifty radiomics features of lung were extracted from treatment planning images, including the positioning CT before radiation therapy (CT1) and the resetting CT after receiving 40 to 45 Gy (CT2). The longitudinal net changes in radiomics features from CT1 to CT2 were calculated and defined as delta-radiomics features. Least absolute shrinkage and selection operator algorithm was performed to features selection and delta-radiomics signature building. Integrating the signature with multidimensional clinicopathologic, dosimetric, and hematological predictors of SARP, a novel CT-based delta-radiomics nomogram was established according to multivariate analysis. The clinical application values of nomogram were both evaluated in the training and validation cohorts by concordance index, calibration curves, and decision curve analysis. Recursive partitioning analysis was used to generate a risk classification system. The delta-radiomics signature consisting of 24 features was significantly associated with SARP status (P < .001). Incorporating it with other high-risk factors, Subjective Global Assessment score, pulmonary fibrosis score, mean lung dose, and systemic immune inflammation index, the developed delta-radiomics nomogram showed increased improvement in SARP discrimination accuracy with concordance index of 0.975 and 0.921 in the training and validation cohorts, respectively. Calibration curves and decision curve analysis confirmed the satisfactory clinical feasibility and utility of nomogram. The risk classification system displayed excellent performance on identifying SARP occurrence (P < .001). The delta-radiomics nomogram and risk classification system as low-cost and noninvasive means exhibited superior predictive accuracy and provided individualized probability of SARP stratification for patients with EC.

Promising Biomarkers of Radiation-Induced Lung Injury: A Review.

Radiation-induced lung injury (RILI) is one of the main dose-limiting side effects in patients with thoracic cancer during radiotherapy. No reliable predictors or accurate risk models are currently available in clinical practice. Severe radiation pneumonitis (RP) or pulmonary fibrosis (PF) will reduce the quality of life, even when the anti-tumor treatment is effective for patients. Thus, precise prediction and early diagnosis of lung toxicity are critical to overcome this longstanding problem. This review summarizes the primary mechanisms and preclinical animal models of RILI reported in recent decades, and analyzes the most promising biomarkers for the early detection of lung complications. In general, ideal integrated models considering individual genetic susceptibility, clinical background parameters, and biological variations are encouraged to be built up, and more prospective investigations are still required to disclose the molecular mechanisms of RILI as well as to discover valuable intervention strategies.

Secondary Infections After Diagnosis of Severe Radiation Pneumonitis (SRP) Among Patients With Non-Small Cell Lung Cancer: Pathogen Distributions, Choice of Empirical Antibiotics, and the Value of Empirical Antifungal Treatment

This study aimed to assess pathogen distributions and antimicrobial sensitivity characteristics in patients with non-small cell lung cancer (NSCLC) with severe radiation pneumonitis (SRP) and secondary infections. Data from 1746 patients with NSCLC and SRP after thoracic radiation therapy from January 2009 to December 2020 were retrospectively analyzed. Pneumonia incidence, causative pathogens, and antibiotic resistance characteristics in patients with secondary lung infections were analyzed. Risk factors associated with mortality were identified through univariate and multivariate analyses. Antifungal drug efficacy and duration-related effects were assessed with Forest plots and receiver operating characteristic curves. Overall, 44.5% of patients with NSCLC and SRP (777 of 1746 patients) were diagnosed with secondary lung infections. In total, 899 bacterial strains were isolated from these patients, with Acinetobacter baumannii (n=206; 27%), Klebsiella pneumonia (n=200; 26.2%), and Pseudomonas aeruginosa (n=104; 13.6%) being the most common. Carbapenem and cefoperazone-sulbactam resistance rates of 52.7% and 32.2%, 28.8% and 26.4%, and 23.7% and 20.2% were observed for these isolates, respectively. Infection-related deaths occurred in 22.4% of patients with SRP. Independent risk factors for infection-related death included poor performance status scores, inappropriate empirical antimicrobial treatment, bacteria/fungal coinfection, and lack of empirical antifungal treatment. Receiver operating characteristic curves showed that the cutoff value of empirical antifungal treatment duration was 9 (area under the curve: 0.819). For patients with SRP and secondary lung infections, appropriate empirical antimicrobial treatment could decrease infection-related mortality, and cefoperazone-sulbactam may be an appropriate antibacterial drug. Empirical antifungal treatment for a minimum of 9 days might contribute to better outcomes. Although this represents a promising treatment approach for patients with SRP and secondary lung infections before antibacterial susceptibility testing, further prospective validation is essential.

PO-1173 Previous pneumectomy is a risk factor of severe radiation pneumonitis after IMRT for lung cancer

PO-1173 Previous pneumectomy is a risk factor of severe radiation pneumonitis after IMRT for lung cancer

Assessment of chemotherapy regimens on radiation pneumonitis in patients with unresectable stage III non-small-cell lung cancer after definitive chemoradiotherapy.

BackgroundConsolidation therapy with durvalumab after concurrent chemoradiotherapy has been reported to significantly prolong progression‐free survival and overall survival in patients with stage III unresectable non‐small cell lung cancer (NSCLC). However, which chemotherapy regimen should be selected for consolidation therapy with durvalumab is currently unknown.MethodsWe retrospectively reviewed consecutive patients with unresectable stage III NSCLC who received concurrent definitive chemoradiotherapy with platinum‐based chemotherapy. We reviewed the timing and severity of radiation pneumonitis by assessing chemotherapy regimens and histology.ResultsA total of 103 patients were identified. Fourteen patients (13.6%) developed grade 2 or greater radiation pneumonitis within 42 days after chemoradiotherapy. No adenocarcinoma patients treated with a regimen of cisplatin plus pemetrexed developed grade 2 or greater radiation pneumonitis within 42 days; however, 20% of patients who were treated with carboplatin plus paclitaxel developed grade 2 or greater radiation pneumonitis. Furthermore, the objective response rates and disease control rates of cisplatin plus pemetrexed were equal to or greater than those of carboplatin plus paclitaxel in adenocarcinoma patients.ConclusionCisplatin plus pemetrexed regimen may be a preferable option to consider for subsequent consolidation therapy with durvalumab in patients with unresectable stage III adenocarcinoma.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

Cytokine Profiles of Non-Small Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy with Regards to Radiation Pneumonitis Severity.

The immunologic aspects of radiation pneumonitis (RP) are unclear. We analyzed variations in cytokine profiles between patients with grade (Gr) 0–1 and Gr ≥ 2 RP. Fifteen patients undergoing concurrent chemoradiotherapy for non-small cell lung cancer were included. Blood samples of 9 patients with Gr 0–1 and 6 with Gr ≥ 2 RP were obtained from the Biobank. Cytokine levels were evaluated using an enzyme linked immunosorbent assay at before radiotherapy (RT) initiation, 1, 3, and 6 weeks post-RT initiation, and 1 month post-RT completion. Concentrations of granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, IL-10, IL-13, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β were analyzed; none were related to the occurrence of Gr ≥ 2 RP at pre-RT initiation. At 3 weeks, relative changes in the G-CSF, IL-6, and IFN-γ levels differed significantly between the groups (p = 0.026, 0.05 and 0.026, respectively). One month post-RT completion, relative changes of IL-17 showed significant differences (p = 0.045); however, relative changes in TNF-α, IL-10, IL-13, and TGF-β, did not differ significantly. Evaluation of changes in IL-6, G-CSF, and IFN-γ at 3 weeks after RT initiation can identify patients pre-disposed to severe RP. The mechanism of variation in cytokine levels in relation to RP severity warrants further investigation.

Severity of radiation pneumonitis, from clinical, dosimetric and biological features: a pilot study

Background and objectiveRadiation pneumonitis (RP) could be a lethal complication of lung cancer treatment. No reliable predictors of RP severity have been recognized. This prospective pilot study was performed to identify early predictors of high grade lung toxicity and to evaluate clinical, biological or dosimetric features associated with different grades of toxicity.MethodSixteen patients with non-small cell lung cancer with indication of concurrent chemoradiotherapy using 60 Gy/2 Gy/fraction starting at cycle one of platinum based chemotherapy were included. Bronchoalveolar lavage (BAL), pulmonary function testing (PFT), and 18F-2-fluoro-2-deoxy-D-glucose positron-emission tomography was performed before radiotherapy (RT), after three weeks of treatment, and two months post-RT. For analysis, patients were grouped by grade (low [G1-G2] vs. high [G3-G5]). The two groups were compared to identify predictors of RP. Protein expression BAL and lung tissue metabolism was evaluated in two patients (RP-G1 vs. RP-G3). Categorical variables such as comorbidities, stages and locations were summarized as percentages. Radiation doses, pulmonary function values and time to RP were summarized by medians with ranges or as means with standard deviation. Longitudinal analysis PFT was performed by a T-test.ResultsAll 16 patients developed RP, as follows: G1 (5 pts; 31.3%); G2 (5 pts; 31.3%); G3 (5 pts; 31.3%); and G5 (1 pts; 6.1%). Patients with high grade RP presented significant decrease (p = 0.02) in diffusing lung capacity for carbon monoxide (DLCO) after three weeks of RT. No correlation between dosimetric values and RP grades was observed. BAL analysis of the selected patients showed that CXCL-1, CD154, IL-1ra, IL-23, MIF, PAI-1 and IFN-γ were overexpressed in the lungs of the RP-G3 patient, even before treatment. The pre-RT SUVmax value in the RP-G3 patient was non-significantly higher than in the patient with RP-G1.ConclusionsRT induces some degree of RP. Our data suggest that decrease in DLCO% is the most sensitive parameter for the early detection of RP. Moreover, we detect biological differences between the two grades of pneumonitis, highlighting the potential value of some cytokines as a prognostic marker for developing high grade lung toxicity. Further multicenter studies with larger sample size are essential to validate these findings.

Factors Associated With Radiation Pneumonitis in Patients Receiving Electron Boost Radiation for Breast-Conserving Therapy: A Retrospective Review

PurposeThis study aimed to investigate risk factors for radiation pneumonitis (RP) caused by electron beam (EB) boost irradiation during breast-conserving therapy. Methods and MaterialsThis single-institution retrospective study included patients with breast cancer treated with breast-conserving therapy from 2013 to 2019. Radiation therapy comprised whole-breast irradiation with a dose of 50 Gy and 10 Gy EB boost dose to the tumor bed. EB energies were 4, 6, 9, 12, and 15 MeV. The lung volume receiving ≥1.25 Gy (V1.25) was calculated and considered because the EB energies have a short range. All patients underwent computed tomography and positron emission tomography/computed tomography within 1 year of irradiation. Imaging evaluation was based on the Common Terminology Criteria for Adverse Events, version 5.0. ResultsOverall, 105 patients (median age, 62 years; range, 33-85) were included for analysis with a median follow-up period of 5 months. Average area of EB boost irradiation was 72 cm2 (range, 36-196). Grade 1 RP developed in the EB irradiation field in 22 (20.6%) patients; grade 2 RP developed in 1 (0.93%) patient. Even in patients with central lung distance (CLD) ≥1.8 cm, a positive correlation was found between RP and both energy (r = 0.36; P = .005) and V1.25 (r = 0.26; P = .04). No correlation was found between RP and irradiation field size (P = .47). The EB energy and V1.25 cutoff values were 12 MeV and 24 cm3, respectively. ConclusionsCLD of ≥1.8 cm, EB energy of ≥12 MeV, and V1.25 of ≥24 cm3 were risk factors associated with RP. Although the frequency of severe RP was not high, patients receiving high-energy electron treatment and those with a large CLD should be closely monitored.

Optimal Management of Radiation Pneumonitis: Preliminary Findings of an International Delphi Consensus Study

Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) and systemic therapy for lung cancer; however, the optimal practice for diagnosis, management and follow-up remains unclear. We sought to establish expert consensus recommendations for RP management. Following literature review on RP, 9 open-ended questions related to knowledge, risk-reduction, diagnosis and treatment were generated for this first round of a consensus-building Delphi process. International leaders in multidisciplinary thoracic oncology were invited to participate (n = 31). Key statements regarding RP diagnosis and management were generated from responses to produce statements for Round 2. Participants will be solicited regarding agreement/disagreement with statements using a 5-point Likert scale. Subsequent rounds will seek consensus in areas that remain unresolved. For Round 1, a 74% response rate (n = 23; 12 radiation oncologists, 5 clinical oncologists, 6 respirologists) was achieved. Eighty-three percent of respondents were not aware of any guidelines for management of RP and 17% used local guidelines or expert review articles. Clinical history, exam and lab criteria (13 respondents) and imaging (15 respondents) were cited as used for diagnosis, and RTOG (9 respondents) and CTCAE grading (14 respondents) for assessment. Radiation-specific factors predictive of RP included irradiated lung volume (especially V20), dose, RT technique and location. The majority of clinical and radiation oncologists used motion management, image guidance and IMRT planning to achieve dosimetric constraints and minimize normal lung dose. Systemic therapy-related RP predictive factors included adjuvant or concurrent chemotherapy, immunotherapy (IO), and use of other pulmonotoxic medications. Patient-related predictive factors included lung function, autoimmune disease, age, performance status and smoking status. Majority of clinicians use risk stratification of patients in order to mitigate RP. Respondents uniformly agreed that steroid therapy is the mainstay of treatment for moderate to severe RP, with variability in the dosing and tapers used. A multidisciplinary management approach was favored by all, including radiation and medical oncologists, respirologists, thoracic radiologists and/or infectious disease or rheumatology specialists if indicated. The majority believe that IO will add complexity in identifying RP. Regarding additional measures to prevent RP in IO patients, respondents were split, with 50% taking additional measures and 50% not, though majority favored monitoring by oncologists during IO cycles and counseling patients on increased RP risk. Responses from international thoracic oncology experts highlight areas lacking consensus in the diagnosis and management of RP. These data will inform the next round of Delphi questions, with an aim of reaching consensus on this common issue.

A missense variant of MASP2 is associated with increased risk of radiation pneumonitis in lung cancer patients treated with radiation therapy*

Abstract Objective In this study, mannan-binding lectin-associated serine protease 2 (MASP2) gene variant was evaluated to assess the risk of radiation pneumonitis (RP) in patients with pulmonary malignancies. Methods A total of 169 lung cancer patients with radiotherapy were included in our prospective study (NCT02490319) and genotyped using the Sanger sequencing method. Multivariate Cox hazards analysis and multiple testing were applied to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of all factors possibly associated with RP risk. Results Patients with mean lung disease ≥ 15 Gy and V20 ≥ 24% had higher risk of RP ≥ grade 2 compared with their 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 + CA genotype of MASP2: rs12711521 was strongly associated with an increased occurrence of RP ≥ grade 2 (HR = 1.949, 95% CI: 1.278-2.971, P = 0.002). Conclusion MASP2: rs12711521 was found to be significantly associated with RP ≥ 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.

The impact of age on the survival outcomes and risk of radiation pneumonitis in patients with unresectable locally advanced non-small cell lung cancer receiving chemoradiotherapy.

BackgroundChemoradiotherapy is the recommended treatment for patients with unresectable locally advanced non-small cell lung cancer (NSCLC). This study aimed to determine the impact of age on the survival outcomes and risk of radiation pneumonitis (RP) in patients with unresectable locally advanced NSCLC.MethodsThe data of patients with unresectable locally advanced NSCLC who were treated with radiotherapy (RT), sequential chemoradiotherapy, or concurrent chemoradiotherapy between January, 2013, and December, 2017, in our institution were retrospectively reviewed and analyzed. Student’s t-test and χ2 test were used to evaluate the differences between groups divided by optimal cutoff. Survival rates were calculated using the Kaplan-Meier method, and multivariate cox regression was performed to determine the prognostic factors for survival outcomes.ResultsA total of 749 patients were included in this analysis. Based on the optimal cutoff, the patients were stratified into two age groups: <65 years old (the younger group, n=482) and ≥65 years old (the older group, n=267). The older group had more patients with poor Karnofsky Performance Score (KPS), squamous cell sarcoma (SCC), and IIIA stage than the younger group. The older patients were more likely to have received RT alone (40.1%) and less likely to have received concurrent chemoradiotherapy (cCRT) (26.6%) than the younger patients (8.1% and 54.8%, respectively, P<0.001). The median overall survival (OS) was 33 months (95% CI: 29–37 months) and 21 months (95% CI: 18–27 months) for the younger group and the older group, respectively (P<0.001). Multivariate Cox regression analysis showed that age had a significant independent association with OS (HR, 1.25; 95% CI: 1.01–1.55) after adjustment for covariates. The incidences of RP, symptomatic RP, and severe RP were similar between the two groups, but the incidence of fatal RP was higher in the older group (4.5% vs. 1.7%, P=0.039).ConclusionsThe clinical characteristics of the older patients in our study differed from those of the younger patients, and the older patients were more likely to choose conservative treatment. OS was longer in the older patients and more cases of fatal RP occurred in the older group.

Analysis of pneumonitis and esophageal injury after stereotactic body radiation therapy for ultra-central lung tumors

ObjectivesSBRT has been associated with serious toxicity in ultra-central lung tumors, but little is known about the incidence and dosimetric correlates of pulmonary and esophageal complications in this setting. Materials and methodsWe retrospectively reviewed SBRT patients whose lung tumor abutted proximal airways, or whose planning target volume overlapped esophagus. All patients received 5–15 fractions of high-dose, image-guided radiation. The primary endpoint was SBRT-related toxicity, with local control and survival as secondary endpoints. ResultsWe included 88 patients. Nineteen patients (22 %) experienced grade ≥3 (G3+) toxicity, including 6 cases of G3+ radiation pneumonitis and 4 cases of G3+ esophageal injury. Two patients developed trachea-esophageal fistula. Overall incidence of radiation pneumonitis was 23 %. Ten patients (11.4 %) succumbed to SBRT-related complications. Multiple dosimetric parameters for lung (including mean lung dose and V20Gy) and esophagus (including maximum point dose) correlated with radiation pneumonitis and esophageal toxicity, respectively. No impact of fractionation on toxicity was seen. ConclusionThis analysis indicates that high rate and multiple manifestations of pulmonary and esophageal toxicity occur after SBRT for ultra-central tumors. In particular, severe radiation pneumonitis and tracheoesophageal fistula are possible. Dosimetric parameters such as mean lung dose and maximum esophageal dose are significantly correlated with toxicity. Further study is needed to optimize the safe delivery of SBRT in these patients.

Radiation pneumonitis after definitive concurrent chemoradiotherapy with cisplatin/docetaxel for non-small cell lung cancer: Analysis of dose-volume parameters.

BackgroundRadiation pneumonitis (RP) is a major pulmonary adverse event of chest radiotherapy. The PACIFIC trial that identified durvalumab as an effective subsequent‐line therapy after concurrent chemoradiotherapy (CCRT) found that patients with grade 2 or higher RP may have to be excluded from treatment under certain criteria. The purpose of this study was to investigate the relationship between grade ≥2 RP and the parameters of dose‐volume histograms after CCRT with cisplatin/docetaxel for stage III non‐small cell lung cancer and conduct a subset analysis of severe RP that can lead to the permanent discontinuation of treatment per the PACIFIC trial criteria to help determine treatment strategy.MethodsWe calculated the percentage of the lung volume received at least 5 Gy (V5) and 20 Gy (V20), the mean lung dose (MLD), and the lung volume spared from a 5 Gy dose (VS5) to the total lung volume. Factors affecting the incidence of grade ≥2 RP were identified; severe RP was defined as grade ≥3 as well as grade 2 RP that required ≥10 mg prednisolone for at least 12 weeks.ResultsThis study included 45 patients. On univariate analysis, all parameters and total lung volume were found to be significant predictors of grade ≥2 RP (P = .001, .003, .03, .004, and .02, respectively). On multivariate analysis, V20 was a significant predictive factor of grade ≥2 RP (P = .007). Severe RP developed in 6 of 37 patients (16.2%) whose V20 values were 35% or lower. On univariate analysis, only V20 was a significant predictor of severe RP in these patients (P = .01).ConclusionsThe best approach to reduce the rate of grade ≥2 RP is to maintain the V5, V20, MLD, and VS5 as low as possible during radiotherapy planning in patients receiving definitive CCRT with cisplatin/docetaxel.

Perspectives on the model-based approach to proton therapy trials: A retrospective study of a lung cancer randomized trial

PurposeThe goal of this study was to assess whether a model-based approach applied retrospectively to a completed randomized controlled trial (RCT) would have significantly altered the selection of patients of the original trial, using the same selection criteria and endpoint for testing the potential clinical benefit of protons compared to photons. Methods and materialsA model-based approach, based on three widely used normal tissue complication probability (NTCP) models for radiation pneumonitis (RP), was applied retrospectively to a completed non-small cell lung cancer RCT (NCT00915005). It was assumed that patients were selected by the model-based approach if their expected ΔNTCP value was above a threshold of 5%. The endpoint chosen matched that of the original trial, the first occurrence of severe (grade ≥3) RP. ResultsOur analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for lung cancer using RP as the normal tissue endpoint. The analyzed lung trial showed that less than 19% (32/165) of patients enrolled in the completed trial would have been enrolled in a model-based trial, prescribing photon therapy to all other patients. The number of patients enrolled was also found to be dependent on the type of NTCP model used for evaluating RP, with the three models enrolling 3%, 13% or 19% of patients. This result does show limitations in NTCP models which would affect the success of a model-based trial approach. No conclusion regarding the development of RP in patients randomized by the model-based approach could statistically be made. ConclusionsUncertainties in the outcome models to predict NTCP are the inherent drawback of a model-based approach to clinical trials. The impact of these uncertainties on enrollment in model-based trials depends on the predicted difference between the two treatment arms and on the set threshold for patient stratification. Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for specific treatment sites, such as lung cancer, depending on the chosen normal tissue endpoint.

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.

Acute severe radiation pneumonitis among non-small cell lung cancer (NSCLC) patients with moderate pulmonary dysfunction receiving definitive concurrent chemoradiotherapy: Impact of pre-treatment pulmonary function parameters.

Severe acute radiation pneumonitis (SARP) is alife-threatening complication of thoracic radiotherapy. Pre-treatment pulmonary function (PF) may influence its incidence. We have previously reported on the incidence of SARP among patients with moderate pulmonary dysfunction who received definitive concurrent chemoradiotherapy (dCCRT) for non-small cell lung cancer (NSCLC). The clinical outcomes, dose-volume histograms (DVH), and PF parameters of 122 patients (forced expiratory volume in 1 s [FEV1%]: 60-69%) receiving dCCRT between 2013 and 2019 were recorded. SARP was defined as grade ≥3RP occurring during or within 3months after CCRT. Logistic regression, receiver operating characteristics curves (ROC), and hazard ratio (HR) analyses were performed to evaluate the predictive value of each factor for SARP. Univariate and multivariate analysis indicated that the ratio of carbon monoxide diffusing capacity (DLCO%; odds ratio [OR]: 0.934, 95% confidence interval [CI] 0.896-0.974, p = 0.001) and mean lung dose (MLD; OR: 1.002, 95% CI 1.001-1.003, p = 0.002) were independent predictors of SARP. The ROC AUC of combined DLCO%/MLD was 0.775 (95% confidence interval [CI]: 0.688-0.861, p = 0.001), with asensitivity and specificity of 0.871 and 0.637, respectively; this was superior to DLCO% (0.656) or MLD (0.667) alone. Compared to the MLD-low/DLCO%-high group, the MLD-high/DLCO%-low group had the highest risk for SARP, with an HR of 9.346 (95% CI: 2.133-40.941, p = 0.003). The DLCO% and MLD may predict the risk for SARP among patients with pre-treatment moderate pulmonary dysfunction who receive dCCRT for NSCLC. Prospective studies are needed to validate our findings.