Combining physical and biologic parameters to predict radiation-induced lung toxicity in patients with non-small-cell lung cancer treated with definitive radiation therapy

Abstract

Purpose: To investigate the plasma dynamics of 5 proinflammatory/fibrogenic cytokines, including interleukin-1beta (IL-1β), IL-6, IL-8, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta1 (TGF-β1) to ascertain their value in predicting radiation-induced lung toxicity (RILT), both individually and in combination with physical dosimetric parameters.

Methods and materials: Treatments of patients receiving definitive conventionally fractionated radiation therapy (RT) on clinical trial for inoperable stages I-III lung cancer were prospectively evaluated. Circulating cytokine levels were measured prior to and at weeks 2 and 4 during RT. The primary endpoint was symptomatic RILT, defined as grade 2 and higher radiation pneumonitis or symptomatic pulmonary fibrosis. Minimum follow-up was 18 months.

Results: Of 58 eligible patients, 10 (17.2%) patients developed RILT. Lower pretreatment IL-8 levels were significantly correlated with development of RILT, while radiation-induced elevations of TGF-ß1 were weakly correlated with RILT. Significant correlations were not found for any of the remaining 3 cytokines or for any clinical or dosimetric parameters. Using receiver operator characteristic curves for predictive risk assessment modeling, we found both individual cytokines and dosimetric parameters were poor independent predictors of RILT. However, combining IL-8, TGF-ß1, and mean lung dose into a single model yielded an improved predictive ability (P<.001) compared to either variable alone.

Conclusions: Combining inflammatory cytokines with physical dosimetric factors may provide a more accurate model for RILT prediction. Future study with a larger number of cases and events is needed to validate such findings.

Fig. 1

The kinetics of plasma cytokines prior to and during 3D conformal RT for patients who did and did not develop RILT. (A) IL-8 plasma levels; (B) TGF-β1 plasma levels; (C) TGF-β1 ratio. Data are means ± standard error of the means.

Fig. 2

ROC curve based on the sensitivity and specificity of pretreatment IL-8 alone, week 2 ratio of TGF-β1 alone, MLD alone, and all 3 parameters combined to predict RILT.