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-β1 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-β1, 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.

Clinical Significance of HMGB-1 and TGF-β Level in Serum and BALF of Advanced Non-Small Cell Lung Cancer

“…Although both HMGB-1 and TGF-β are involved with cancer progression, they act in different ways (Stenmark et al 2013;Liu et al 2012a). HMGB-1 activates neoangiogenesis, migration, and proliferation of cancer cells, and enhances their ability to escape immune surveillance (Smolarczyk et al 2012).…”

“…Although this tendency did not reach statistical significance in our study, it is in line with the results of Vazquez et al (2013) who confirmed the high level of TGF-β in lung cancer patients augurs worse. While the evidence of a prognostic value of HMGB-1 specifically in NSCLC patients has not yet been reported, there are reports that its increase is associated with a decreased survival time of patients with bladder, stomach, nasopharynx, and liver cancers (Stenmark et al 2013;Liu et al 2012a). …”

TGFβ Inhibition Prior to Hypofractionated Radiation Enhances Efficacy in Preclinical Models

“…In addition, TGFb promotes alternative macrophage differentiation and decreases antigen presentation and effector function, while increasing macrophage trafficking to the site of inflammation (23,24). TGFb inhibitors have been combined with radiotherapy in preclinical cancer models and have increased radiosensitivity and reduced radiation-related mucositis, pneumonitis, and fibrosis (25)(26)(27)(28)(29)(30).…”

ATM and TGFB1 genes polymorphisms in prediction of late complications of chemoradiotherapy in patients with locally advanced cervical cancer

“…Numerous studies reporting the association between high TGFB1 plasma levels in cancer patients and the development of severe radiation-induced fibrosis demonstrated the involvement of TGFB1 and its functional polymorphisms in clinical radiosensitivity. Theses studies included patients treated by radiotherapy for lung cancer [12,13], prostate 14], head and neck cancer [15], breast cancer [16,17], rectal cancer [18]. However, other studies have been somewhat confusing [19].…”