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

Abstract

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.

Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non–Small-cell Lung Cancer

“…The risk factors for radiation pneumonitis have been reported to include the timing and schedule of RT sessions, the mean lung dose, the target volume and dose, pre-existing lung disease, and circulating cytokines. [22][23][24] The risk factors for immunotherapy-related pneumonitis have not been defined; however, suggestions have included active smoking, which we were unable to confirm in our study. 25 Little is known about which risk factors increase the likelihood of irAEs overall and pneumonitis in particular, and what effect irAEs might have on survival.…”

Machine Learning to Build and Validate a Model for Radiation Pneumonitis Prediction in Patients with Non–Small Cell Lung Cancer

“…In our study, lower IL8 level was found statistically significant with higher risk of RP2, which is consistent with previous literature on RILT. Both of our previous studies (8,37) and Hart and colleagues (38) had reported that low IL8 was correlated with an increased risk of RILT. IL8 has chemotactic activity for leukocytes and induces collagen synthesis and cell proliferation (39) in animal studies, but it has been consistently found to have an antiinflammatory effect in humans (12,37,38,40).…”

“…Both of our previous studies (8,37) and Hart and colleagues (38) had reported that low IL8 was correlated with an increased risk of RILT. IL8 has chemotactic activity for leukocytes and induces collagen synthesis and cell proliferation (39) in animal studies, but it has been consistently found to have an antiinflammatory effect in humans (12,37,38,40). Furthermore, it has been shown that neutrophils penetrate the injury site and perform the critical tasks of dismantling injured vessels and creating channels for new vascular regrowth, which is important for full repair of the sterile injury (41).…”

“…First, definitions of radiation pneumonitis and RILT were not consistent as described in the Introduction section, which may have confounded the results. The role of TGFb1 may be more prominent for fibrosis (37,43). Second, TGFb1 can be produced by both tumor and normal tissues, which seriously confound its role on RP2.…”

Ensuring sample quality for blood biomarker studies in clinical trials: a multicenter international study for plasma and serum sample preparation

“…It is known that there are remarkable differences between serum and plasma proteomes [17][18][19][20][21]. In the present study, poorly prepared plasma samples (as described above with blood samples either sitting at room temperature or inadequately centrifuged) had a different protein profile from that of good plasma samples (Figure 4).…”