Nondosimetric Risk Factors for Radiation-Induced Lung Toxicity

Kong, Feng-Ming; Wang, Shulian

doi:10.1016/j.semradonc.2014.12.003

Cited by 116 publications

(99 citation statements)

References 100 publications

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“…Dosimetric factors especially mean lung dose (MLD) have been consistently correlated with the risk of RILT [1, 2]. Other factors, such as older age, pre-existing interstitial lung disease, tumor located in lower lung and concurrent taxane chemotherapy, have been shown to be associated with RILT [3]. Inflammatory cytokines play important roles in the biological processes of radiation lung damage, damage repair and clinical toxicity.…”

Section: Introductionmentioning

confidence: 99%

Plasma Levels of IL-8 and TGF-β1 Predict Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer: A Validation Study

Wang

Campbell

Stenmark

et al. 2017

International Journal of Radiation Oncology*Biology*Physics

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Purpose/Objectives We previously reported that combination of mean lung dose (MLD), and inflammatory cytokines (IL-8 and TGF-β1) may provide a more accurate model for radiation-induced lung toxicity (RILT) prediction in 58 patients with non-small cell lung cancer (NSCLC). This study is to validate the previous findings with new patients and explore new models with more cytokines. Materials/Methods 142 patients with stage I–III NSCLC treated with definitive radiation therapy (RT) from prospective studies were included. Sixty-five new patients were used to validate previous findings, and all 142 patients to explore new models. Thirty inflammatory cytokines were measured in plasma samples before RT, 2 weeks and 4 weeks during RT (pre, 2w, 4w). Grade ≥2 RILT defined as grade 2 and higher radiation pneumonitis or symptomatic pulmonary fibrosis was the primary endpoint. Logistic regression was performed to evaluate the risk factors of RILT. The area under the curve (AUC) for the Receiver Operating Characteristic (ROC) curves was used for model assessment. Results Sixteen of 65 patients (24.6%) developed RILT2. Lower pre IL-8 and higher TGF-β1 2w/pre ratio were associated with higher risk of RILT2. The AUC increased to 0.73 by combining MLD, pre IL-8 and TGF-β1 2w/pre ratio compared with 0.61 by MLD alone to predict RILT. In all 142 patients, 29 patients (20.4%) developed grade ≥2 RILT. Among the 30 cytokines measured, only IL-8 and TGF-β1 were significantly associated with the risk of RILT2. MLD, pre IL-8 level and TGF-β1 2w/pre ratio were included in the final predictive model. The AUC increased to 0.76 by combining MLD, pre IL-8 and TGF-β1 2w/pre ratio compared with 0.62 by MLD alone. Conclusions We validated that a combination of mean lung dose, pre IL-8 level and TGF-β1 2w/pre ratio provided a more accurate model to predict the risk of RILT2 compared to MLD alone.

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Section: Introductionmentioning

confidence: 99%

Plasma Levels of IL-8 and TGF-β1 Predict Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer: A Validation Study

Wang

Campbell

Stenmark

et al. 2017

International Journal of Radiation Oncology*Biology*Physics

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“…Normal tissue toxicity, however, limits this approach. The most common dose limiting adverse events are pulmonary pneumonitis and fibrosis [2]. Pneumonitis can develop within weeks of irradiation and in many, but not all cases is reversible.…”

Section: Introductionmentioning

confidence: 99%

“…Pneumonitis can develop within weeks of irradiation and in many, but not all cases is reversible. Fibrosis can develop months to years after treatment, is not reversible but progressive, and can lead to permanent impairment of lung function [2]. Currently, the biological factors that are critical for repair and renewal of distal epithelial tissue following radiation injury are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung

Traver

Mont

Gius

et al. 2017

Free Radical Biology and Medicine

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The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2flox/flox, and Nrf2Δ/Δ; SPC-Cre) were administered a thoracic dose of 12 Gy and allowed to recover for 250 days. Whole slide digital and confocal microscopy imaging of H&E, Masson’s trichrome and immunostaining were used to assess tissue remodeling, collagen deposition and cell renewal/mobilization during the regenerative process. Histological assessment of irradiated, fibrotic wild type lung revealed significant loss of alveolar type 2 cells 250 days after irradiation. Type 2 cell loss and the corresponding development of fibrosis were enhanced in the Nrf2 null mouse. Yet, conditional deletion of Nrf2 in alveolar type 2 cells in irradiated lung did not impair type 2 cell survival nor yield an increased fibrotic phenotype. Instead, radiation-induced ΔNp63 stem/progenitor cell mobilization was inhibited in the Nrf2 null mouse while the propensity for radiation-induced myofibroblasts derived from alveolar type 2 cells was magnified. In summary, these results indicate that Nrf2 is an important regulator of irradiated lung’s capacity to maintain alveolar type 2 cells, whose injury can initiate a fibrotic phenotype. Loss of Nrf2 inhibits ΔNp63 stem/progenitor mobilization, a key event for reconstitution of injured lung, while promoting a myofibroblast phenotype that is central for fibrosis.

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“…16 All reported P values are two-sided, and all statistical analyses were performed using SPSS version 20 software (IBM Corp., Armonk, NY). The overall survival duration was defined as the period from RT completion to the time of death, and the Kaplan-Meier method was used to calculate the overall survival rate.…”

Section: Discussionmentioning

confidence: 99%

“…5,16 Despite applying a validated dosimetric guideline, some patients still experience symptomatic RP; therefore, nondosimetric risk factors have been deemed more accurate predictors of RP progression. 5,16 Despite applying a validated dosimetric guideline, some patients still experience symptomatic RP; therefore, nondosimetric risk factors have been deemed more accurate predictors of RP progression.…”

Section: Discussionmentioning

confidence: 99%