Significance of plasma transforming growth factor-β levels in radiotherapy for non–small-cell lung cancer

Abstract

Purpose In dose-escalation studies of radiotherapy (RT) for non–small-cell lung cancer (NSCLC), radiation pneumonitis (RP) is the most important dose-limiting complication. Transforming growth factor-β1 (TGF-β1) has been reported to be associated with the incidence of RP. It has been proposed that serial measurements of plasma TGF-β1 can be valuable to estimate the risk of RP and to decide whether additional dose-escalation can be safely applied. The aim of this study was to evaluate prospectively the time course of TGF-β1 levels in patients irradiated for NSCLC in relation to the development of RP and dose–volume parameters. Methods and materials Plasma samples were obtained in 68 patients irradiated for medically inoperable or locally advanced NSCLC (dose range, 60.8–94.5 Gy) before and 4, 6, and 18 weeks after the start of RT. Plasma TGF-β1 levels were determined using a bioassay on the basis of TGF-β1-induced plasminogen activator inhibitor-1 expression in mink lung cells. All patients underwent chest computed tomography scans before RT that were repeated at 18 weeks after RT. The computed tomography data were used to calculate the mean lung dose (MLD) and to score the radiation-induced radiologic changes. RP was defined on the basis of the presence of either radiographic changes or clinical symptoms. Symptomatic RP was scored according to the Common Toxicity Criteria (Grade 1 or worse) and the Southwestern Oncology Group criteria (Grade 2 or worse). Multivariate analyses were performed to investigate which factors (pre- or posttreatment TGF-β1 level, MLD) were associated with the incidence of RP. To improve our understanding of the time course of TGF-β1 levels, we performed a multivariate analysis to investigate which factors (pre-RT TGF-β1 level, MLD, RP) were independently associated with the posttreatment TGF-β1 levels. Results The pre-RT TGF-β1 levels were increased in patients with NSCLC (median 21 ng/mL, range, 5–103 ng/mL) compared with healthy individuals (range, 4–12 ng/mL). On average, the TGF-β1 levels normalized toward the end of treatment and remained stable until 18 weeks after RT. In 29 patients, however, TGF-β1 was increased at the end of RT with respect to the pre-RT value. The multivariate analyses revealed that the MLD was the only variable that correlated significantly with the risk of both radiographic RP ( p = 0.05) and symptomatic RP, independent of the scoring system used ( p = 0.05 and 0.03 for Southwestern Oncology Group and Common Toxicity Criteria systems, respectively). The TGF-β1 level at the end of RT was significantly associated with the MLD ( p <0.001) and pre-RT TGF-β1 level ( p = 0.001). Conclusion The MLD correlated significantly with the incidence of both radiographic and symptomatic RP. The results of our study did not confirm the reports that increased levels of TGF-β1 at the end of RT are an independent additional risk factor for developing symptomatic RP. However, the TGF-β1 level at the end of a RT was significantly associated with the MLD and the pre-RT level.