Symptomatic Radiation-induced Lung Injury Research Articles

Predictive factors for severe radiation-induced lung injury in patients with lung cancer and coexisting interstitial lung disease

Background and purposeThis study aimed to investigate the predictive factors of severe radiation-induced lung injury (RILI) in patients with lung cancer and coexisting interstitial lung disease (ILD) undergoing conventionally fractionated thoracic radiotherapy. Materials and methodsThe study includes consecutive patients treated with thoracic radiotherapy for lung cancer at two tertiary centers between 2010 and 2021. RILI severity was graded using the National Cancer Institute Common Terminology Criteria version 5.0, with severe RILI defined as toxicity grade ≥4, and symptomatic RILI as grade ≥2. The absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and C-reactive protein were collected within 4 weeks before starting radiotherapy. Neutrophil–lymphocyte ratios (NLR) were calculated as ANC/ALC. The median follow-up was 9 (range, 6–114) months. ResultsAmong 54 patients, 22 (40.7 %) had severe RILI. On multivariate logistic regression analysis, high pretreatment ANC (p = 0.030, OR = 4.313), pretreatment NLR (p = 0.007, OR = 5.784), and ILD severity (p = 0.027, OR = 2.416) were significant predictors of severe RILI. Dosimetric factors were not associated with severe RP. Overall survival was significantly worse for patients with severe RILI than those without, with 1-year cumulative overall survival rates of 7.4 % and 62.8 %, respectively. ConclusionPretreatment blood NLR, ANC, and ILD severity were associated with severe RILI. Overall survival was dismal for patients with severe RILI.

The dose\u2013response characteristics of four NTCP models: using a novel CT-based radiomic method to quantify radiation-induced lung density changes

Multiple competing normal tissue complication probability (NTCP) models have been proposed for predicting symptomatic radiation-induced lung injury in human. In this paper we tested the efficacy of four common NTCP models applied quantitatively to sub-clinical X-ray computed tomography (CT)-density changes in the lung following radiotherapy. Radiotherapy planning datasets and follow-up chest CTs were obtained in eight patients treated for targets within the lung or hilar region. Image pixel-wise radiation dose exposure versus change in observable CT Hounsfield units was recorded for early (2–5 months) and late (6–9 months) time-points. Four NTCP models, Lyman, Logistic, Weibull and Poisson, were fit to the population data. The quality of fits was assessed by five statistical criteria. All four models fit the data significantly (p < 0.05) well at early, late and cumulative time points. The Lyman model fitted best for early effects while the Weibull Model fitted best for late effects. No significant difference was found between the fits of the models and with respect to parameters D50 and γ50. The D50 estimates were more robust than γ50 to image registration error. For analyzing population-based sub-clinical CT pixel intensity-based dose response, all four models performed well.

Predictive factors for radiation-induced lung injury in locally advanced non-small cell lung cancer after intensity-modulated radiotherapy

Objective To investigate the incidence of radiation-induced lung injury (RILI) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after involved-field intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy, and to figure out the predictive factors for RILI. Methods Two hundred and fifty-six patients with stage Ⅲ NSCLC who were treated without surgery in our hospital from January 2007 to December 2011 were enrolled as subjects. All patients received involved-field IMRT with a median dose of 60 Gy (50-70 Gy) in 30 fractions. In all patients, 109 patients (42.6%) received concurrent chemotherapy. The National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 was used to evaluate the RILI grade. The incidence of grade ≥2 RILI (symptomatic RILI, SRILI) within 6 months after radiotherapy served as the end point. The predictive factors for RILI were analyzed using logistic regression model. Results In all patients, 215(84%) were male, and 41(16%) were female. The mean age at diagnosis was 59.2 years. Forty-three (16.7%) patients had grade ≥2 RILI. The mean duration between the incidence of RILI and the beginning of radiotherapy was 64 days (20-169 days). Univariate analysis showed that smoking, peripheral or central tumor location, mean lung dose (MLD) for both lungs, and V5-V20 for both lungs were suspected to be associated with the development of SRILI (P=0.108, 0.106, 0.030, 0.049). Multivariate analysis showed the MLD and V5-V20 for both lungs were independent predictive factors for SRILI P=(0.048). Conclusions For patients with LA-NSCLC treated with involved-field IMRT, the MLD and the volume of low-dose region in dose volume histogram for both lungs are significantly correlated with the incidence of SRILI. Key words: Cacinoma, non-small cell lung/intensity modulated radiotherapy; Cacinoma, non-small cell lung/chemotherapy; Symptomatic radiation induced lung injury

Analysis of Clinical and Dosimetric Factors Influencing Radiation-Induced Lung Injury in Patients with Lung Cancer.

Purpose: Dose escalation of thoracic radiation can improve the local tumor control and surivival, and is in the meantime limited by the occurrence of radiation-induced lung injury (RILI). This study investigated the clinical and dosimetric factors influencing RILI in lung-cancer patients receiving chemoradiotherapy for better radiation planning.Methods and Materials: A retrospective analysis was carried out on 161 patients with non-small-cell or small-cell lung cancer (NSCLC and SCLC, respectively), who underwent chemoradiotherapy between April 2010 and May 2011 with a median follow-up time of 545 days (range: 39-1453). Chemotherapy regimens were based on the histological type (squamous cell carcinoma, adenocarcinoma, or SCLC), and radiotherapy was delivered in 1.8-3.0 Gy (median, 2.0 Gy) fractions, once daily, to a total of 39-66 Gy (median, 60 Gy). Univariate analysis was performed to analyze clinical and dosimetric factors associated with RILI. Multivariate analysis using logistic regression identified independent risk factors correlated to RILI.Results: The incidence of symptomatic RILI (≥grade 2) was 31.7%. Univariate analysis showed that V5, V20, and mean lung dose (MLD) were significantly associated with RILI incidence (P=0.029, 0.048, and 0.041, respectively). The association was not statistically significant for histological type (NSCLC vs. SCLC, P = 0.092) or radiation technology (IMRT vs. 3D-CRT, P = 0.095). Multivariate analysis identified MLD as an independent risk factor for symptomatic RILI (OR=1.249, 95%CI=1.055-1.48, P= 0.01). The incidence of bilateral RILI in cases where the tumor was located unilaterally was 22.7% (32/141) and all dosimetric-parameter values were not significantly different (P>0.05) for bilateral versus ipsilateral injury, except grade-1 (low) RILI (P < 0.05). The RILI grade was higher in cases of ipsilateral lung injury than in bilateral cases (Mann-Whitney U test, z=8.216, P< 0.001).Conclusion: The dosimetric parameter, MLD, was found to be an independent predictive factor for RILI. Additional contralateral injury does not seem to be correlated with increased RILI grade under the condition of conventional radiotherapy treatment planning.

Pulmonary damage in Hodgkin's lymphoma patients treated with sequential chemo-radiotherapy: Predictors of radiation-induced lung injury

Background. Our aim was to define predictors of late radiation-induced lung injury (RILI) in Hodgkin's lymphoma (HL) survivors treated with bleomycin-containing chemotherapy and radiotherapy. Material and methods. Eighty consecutive patients treated with chemotherapy and subsequent supradiaphragmatic radiation therapy for HL were retrospectively reviewed for symptoms and/or radiological signs of RILI. Median patient age was 26 years (range 14–55). Left, right, and total lung dosimetric parameters along with clinical, disease, and treatment-related characteristics were analyzed. Multivariate logistic regression analyses were performed. A receiver operator characteristic (ROC) curve analysis was performed to find possible cutoff values dividing patients into high- and low-risk groups. Results. Seven of 80 (9%) patients had lung disease at baseline. Four of 80 (5%) had toxicity after chemotherapy and before the beginning of radiotherapy. These patients were excluded from further evaluation. At a median time of 10 months (range 9–18), 9/69 patients (13%) developed lung radiological changes on computed tomography (CT) after treatment. Four of nine patients were diagnosed RTOG grade ≥ 2. On multivariate analyses, left-lung V30 (p = 0.004, OR = 1.108 95% CI 1.033–1.189) and total-lung V30 (p = 0.009, OR = 1.146 95% CI 1.035–1.270) resulted to be predictors of lung CT changes with a cutoff value of 16% and 15%, respectively. When only symptomatic RILI was considered a left-lung V30 cutoff value of 32% was estimated. Conclusion. Bleomycin and RT may cause lung injury in a small, but significant fraction of HL patients. Left-lung V30 predicts the risk of developing asymptomatic or symptomatic RILI after sequential chemo-radiotherapy.

Management and outcome of symptomatic radiation induced lung injury in non-small cell lung cancer

Objective To analyze the management and outcome of symptomatic radiation-induced lung injury (SRILI) in non-small cell lung cancer (NSCLC).Methods Between 2000 and 2007,80 NSCLC patients,who developed SRILI with detailed record,were enrolled into the analysis.The classification of RILI was evaluated according to common terminology criteria for adverse events,version 3.0.Asame patient might be assigned into more than one grade of SRILI classification for analysis as he or she experienced more than one phase of RILI during the disease course.There were grade 2 (G2),G3,G4 and G5 SRILI,which were seen in 49,46,1 and 4 patients,respectively.Results Eighty-seven percent of patients with G3SR[LI and three patients with G2 SRILI accompaniedwith fever were treated with corticosteroid.Some of them received prophylactic administration of first-line antibiotics.The initial dose of steroid ranged from 20 to 66.7 mg prednisone equivalent daily; the median effective dose was 33.3mg daily.The dose of steroid decreased by slow taper; the median duration of treatment was 33 days.Of the 34 patients who underwent steroid treatment and received evaluation of response to steroid treatment,65％ were steroid-sensitive,and 32％ were steroid-dependent.Thirty-one percent of patients with G2 SRILI progressed to G3,and 9％ of patients with G3 SRILI upgraded to G5.Conclusions Corticosteroid is the primary therapy for G3 SRILI and may also be considered for G2 SRILI accompanied with fever.Meanwhile,prophylactic administration of first-line antibiotics can be chosen.Steroid is effective in the treatment of SRILI,and SRILI related mortality is low with timely steroid treatment. Key words: Radiation-induced lung injury/hormone therapy ; Management; Outcome; Lung neoplasms/radiotherapy

Analysis of clinical characteristics of symptomatic radiation-induced lung injury in patients with non-small cell lung cancer after radiotherapy

Objective To analyze the clinical characteristics of symptomatic radiation-induced lung injury (SRILI) in patients with non-small cell lung cancer (NSCLC) after radiotherapy.Methods A retrospective analysis was performed on the patients with NSCLC who received radiotherapy in our hospital from January 2000 to May 2007 and who developed SRILI during therapy or follow-up and received related treatment in our hospital.The symptoms,clinical signs,imaging findings,and hematological changes of the patients were observed.The SRILI was diagnosed and classified by 2 radiation oncologists and 1 radiologist according to CTC 3.0 criteria.Results A total of 81 SRILI patients were included in the analysis.Of them,35 had grade 2 SRILI,42 had grade 3 SRILI,0 had grade 4 SRILI,and 4 had grade 5 SRILI.The median time from beginning of radiotherapy to onset of SRILI symptoms was 8.3 weeks (ranging from 1.3 to 32.3 weeks).Among the SRILI symptoms,cough was observed in 95％ of the patients,short breath in 69％ of the patients,and fever in 48％ of the patients.The median highest body temperature was 38.3℃.The clinical signs,found in relatively few patients,included coarse breath sound as the common one,seen in about 50％ of the patients.The imaging findings included lung consolidation,air bronchogram,patchy opacities,and linear opacities,most of which were found in the radiation field.The hematological changes included slightly elevated percentage of neutrophils (median =77.4％).Conclusions The symptoms of SRILI occurred at 8.3 (median) weeks after the beginning of radiation.The clinical characteristics of SRILI include cough,short breath,fever,coarse breath sound,imaging findings of lung consolidation,patchy opacities,and linear opacities,which are mostly found in the radiation field,and slightly elevated percentage of neutrophils. Key words: Lung neoplasms/radiotherapy; Radiation-induced lung injury; Clinical characteristics

Preliminary Study of Protective Effects of Flavonoids against Radiation-induced Lung Injury in Mice

Radiation therapy plays an important role in lung carcinoma treatment. However, the incidence of symptomatic radiation-induced lung injury is high. This study aimed to evaluate radioprotective effects of flavonoids extracted from Astragalus complanatus and mechanisms of action against radiation damage. Alteration in antioxidant status and levles of several cytokines were investigated in BABL/C mice treated with 4 mg/kg b.wt. flavonoids after exposure to 10Gy thoracic radiation. Serum levels of SOD in the flavonoids+radiation group were significantly higher compared to the radiation control group, while TGF-β1 and IL-6 were lower. Mice in the radiation control group displayed more severe lung damage compared with the flavonoids+radiation group. The expression of TGF-β1 and TNF-α in the radiation control group was markedly increased in alveolar epithelial cells and macrophages of the alveolar septum. From the results of the present study, flavonoids could be excellent candidates as protective agents against radiation-induced lung injury.

Cytokine profiling for prediction of symptomatic radiation-induced lung injury

To analyze plasma cytokine profiles before the initiation of radiation therapy to define a cytokine phenotype that correlates with risk of developing symptomatic radiation-induced lung injury (SRILI). Symptomatic radiation-induced lung injury was evaluated in 55 patients (22 with SRILI and 33 without SRILI), according to modified National Cancer Institute common toxicity criteria. These plasma samples were analyzed by the multiplex suspension bead array system (Bio-Rad Laboratories; Hercules, CA), which included the following cytokines: interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17, granulocyte/macrophage colony-stimulating factor, interferon-gamma, monocyte chemotactic protein 1, macrophage inflammatory protein 1beta, tumor necrosis factor alpha, and granulocyte colony-stimulating factor. Significant differences in the median values of IL-8 were observed between patients with and without SRILI. Patients who did not develop SRILI had approximately fourfold elevated levels of IL-8 as compared with patients who did subsequently develop SRILI. Significant correlations were not found for any other cytokine in this study, including transforming growth factor beta1. Patients with lower levels of plasma IL-8 before radiation therapy might be at increased risk for developing SRILI. Further studies are necessary to determine whether IL-8 levels are predictive of SRILI in a prospective trial and whether this marker might be used to determine patient eligibility for dose escalation.

Predicting the risk of symptomatic radiation-induced lung injury using both the physical and biologic parameters V 30 and transforming growth factor β

Purpose: To correlate the volume of lung irradiated with changes in plasma levels of the fibrogenic cytokine transforming growth factor β (TGFβ) during radiotherapy (RT), such that this information might be used to predict the development of symptomatic radiation-induced lung injury (SRILI). Methods and Materials: The records of all patients with lung cancer treated with RT with curative intent from 1991 to 1997 on a series of prospective normal tissue injury studies were reviewed. A total of 103 patients were identified who met the following inclusion criteria: ( 1) newly diagnosed lung cancer of any histology treated with RT ± chemotherapy with curative intent; ( 2) no evidence of distant metastases or malignant pleural effusion; ( 3) no thoracic surgery after lung RT; ( 4) no endobronchial brachytherapy; ( 5) follow-up time more than 6 months; ( 6) plasma TGFβ1 measurements obtained before and at the end of RT. The concentration of plasma TGFβ1 was measured by an enzyme-linked immunosorbent assay. Seventy-eight of the 103 patients were treated with computed tomography based 3-dimensional planning and had dose–volume histogram data available. The endpoint of the study was the development of SRILI (modified NCI [National Cancer Institute] common toxicity criteria). Results: The 1-year and 2-year actuarial incidence of SRILI for all 103 patients was 17% and 21%, respectively. In those patients whose TGFβ level at the end of RT was higher than the pre-RT baseline, SRILI occurred more frequently (2-year incidence = 39%) than in patients whose TGFβ1 level at the end of RT was less than the baseline value (2-year incidence = 11%, p = 0.007). On multivariate analysis, a persistent elevation of plasma TGFβ1 above the baseline concentration at the end of RT was an independent risk factor for the occurrence of SRILI ( p = 0.004). The subgroup of 78 patients treated with 3-dimensional conformal radiotherapy, who consequently had dose–volume histogram data, were divided into groups according to their TGFβ1 kinetics and whether their V 30 level was above or below the median of 30%. Group I ( n = 29), with both a TGFβ1 level at the end of RT that was below the pre-RT baseline and V 30 < 30%; Group II ( n = 35), with a TGFβ1 level at the end of irradiation that was below the baseline but a V 30 ≥ 30% or with a TGFβ1 level at the end of RT that was above the pre-RT baseline but V 30 < 30%; Group III ( n = 14), with both a TGFβ1 level at the end of RT that was above the baseline and V 30 ≥ 30%. A significant difference was found in the incidence of SRILI among these three groups (6.9%, 22.8%, 42.9%, respectively, p = 0.02). Conclusions: ( 1) An elevated plasma TGFβ1 level at the end of RT is an independent risk factor for SRILI; ( 2) The combination of plasma TGFβ1 level and V 30 appears to facilitate stratification of patients into low, intermediate, and high risk groups. Thus, combining both physical and biologic risk factors may allow for better identification of patients at risk for the development of symptomatic radiation-induced lung injury.

Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor ( M6P/IGF2R) locus predisposes patients to radiation-induced lung injury

Purpose: To investigate the relationship between loss of heterozygosity (LOH) at the mannose 6-phosphate/insulin-like growth factor 2 receptor ( M6P/IGF2R) gene locus and the development of radiation-induced lung injury. Material and Methods: Thirty-five lung cancer patients with both stored plasma for Transforming Growth Factor β1 (TGFβ1) analysis and sufficient quantities of archival pathology tissue to screen for LOH were studied. All patients had been treated with thoracic radiotherapy for their malignancy and had radiographically detectable tumor present before beginning radiotherapy. Tumor and normal cells were microdissected from archival lung cancer pathology specimens. Two polymorphisms in the 3′ untranslated region of the M6P/IGF2R were used to screen for LOH. Plasma TGFβ1 levels were measured using acid-ethanol extraction and an ELISA. TGFβ1 and M6P/IGF2R protein expression was estimated by immunofluorescence and immunohistochemical staining. Symptomatic radiation pneumonitis was scored according to National Cancer Institute Common Toxicity Criteria without knowledge of the results of TGFβ or LOH analyses. Results: Of the 35 patients, 10 were homozygous for this polymorphism (noninformative) and were excluded. Of the 25 informative patients, 13 had LOH. Twelve of 13 patients with LOH had increased pretreatment plasma TGFβ1 levels, vs. 3/12 patients without LOH ( p < 0.01). A decrease or loss of M6P/IGF2R protein in the malignant cell accompanied by increased latent TGFβ1 protein in extracellular matrix and tumor stroma was found in tumors with LOH, suggesting that this mutation resulted in loss of function of the receptor. Seven of 13 (54%) LOH patients developed symptomatic radiation-induced lung injury vs. 1/12 (8%) of patients without LOH ( p = 0.05). Conclusions: Loss of the M6P/IGF2R gene strongly correlates with the development of radiation pneumonitis after thoracic radiotherapy (RT). Furthermore, patients with LOH (in the setting of measurable tumor) are much more likely to have elevated plasma TGFβ, suggesting an inability to normally process this cytokine. Thus, loss of the M6P/IGF2R gene may predispose patients to the development of radiation-induced lung injury.

Can angiotensin-converting enzyme inhibitors protect against symptomatic radiation pneumonitis?

This study was designed to determine whether patients taking angiotensin-converting enzyme (ACE) inhibitors while receiving radiation therapy for lung cancer are protected from developing symptomatic radiation pneumonitis. The records of 213 eligible patients receiving thoracic irradiation for lung cancer with curative intent at Duke University Medical Center from 1994-1997 were reviewed. Of the 213 patients, 26 (12.2%) were on ACE inhibitors (usually for the management of hypertension) during radiotherapy (group 1); the remaining 187 patients (group 2) were not. Patients were irradiated, with fields shaped to protect normal tissues, with total doses of 50-80 Gy. After treatment, patients were generally followed every 3 months for 2 years, then every 6 months thereafter. Symptomatic radiation pneumonitis was scored according to modified National Cancer Institute Common Toxicity Criteria (i.e., radiographic changes alone were not sufficient for the diagnosis of pneumonitis). There was no difference in the incidence of pneumonitis between the two groups (P = 0.75). Fifteen percent of the patients on ACE inhibitors (group 1) developed symptomatic radiation-induced lung injury compared to 12% of the patients not receiving these drugs (group 2). Although patients in group 1 tended to develop pneumonitis slightly sooner than did patients in group 2, this difference also was not significant (P = 0. 8). Within the dose range prescribed for treating hypertension, ACE inhibitors do not appear to either decrease the incidence or delay the onset of symptomatic radiation pneumonitis among lung cancer patients receiving thoracic irradiation.