肺剂量和炎性细胞因子在预测放疗诱导性肺毒性中的临床价值

目的分析平均肺剂量(MLD)和炎性细胞因子(IL-8和TGF-β1)组合预测放射性肺损伤(radiation-induced lung injury, RILT)的准确性和有效性。 方法选择75例Ⅰ-Ⅲ期的NSCLC患者，通过使用三维适形技术给予放射疗法，在4～7周内每天以2.0～2.9 Gy的剂量递送44～87.9 Gy给患者。分别提取患者放射治疗前(pre)，放射治疗2周(2 W)，4周(4 W)的血液样品，测定细胞因子的表达含量。患者随访接受病史检查和体格检查以及胸部计算机断层扫描，随访终点为出现RILT症状，或肺炎、肺纤维化等症状。Logistic回归分析平均肺剂量(MLD)和炎性细胞因子(IL-8和TGF-β1)的表达变化以评估其与RILT的相关性，ROC曲线下面积(AUC)用于分析这些因素在预测RILT的特异性和敏感性。 结果75例Ⅰ-Ⅲ期的NSCLC患者中65例出现RILT ，其中16例(24.6%)患者的RILT等级大于2。MLD，基线IL-8水平和TGF-β1 2 W/pre比率的AUC值分别为0.61(0.45，0.77)，0.70(0.56，0.84)和0.68(0.53，0.83)。与MLD单独预测相比，MLD，基线IL-8水平和TGF-β1 2w/pre比率组合可将AUC的值从0.61提高到0.73(0.60，0.87)。 结论IL-8和TGF-β1是NSCLC患者RILT的重要预测因子。MLD，IL-8水平和TGF-β1 2 W/pre比率的组合提供了更准确的模型来预测RILT2的风险。

Clinical value of lung dose and inflammatory cytokines in predicting radiotherapy-induced pulmonary toxicity

ObjectiveRadiotherapy(RT) remains an important and potentially curative treatment for localized and locally advanced non-small cell lung cancer (NSCLC), but radiotherapy-induced lung toxicity (RILT) is one of the dose-limiting toxicities for radiotherapy in patients with non-small cell lung cancer. This study is to analyze the accuracy and effectiveness of the combination of mean lung dose (MLD) and inflammatory cytokines (IL-8 and TGF-β1) in predicting radiation-induced lung toxicity (RILT). Methods75 patients with stage Ⅰ-Ⅲ NSCLC treated with definitive radiotherapy (RT) were included in this study. Treatments of patients receiving definitive conventionally fractionated radiotherapy on a clinical trial for inoperable stages Ⅰ-Ⅲ lung cancer were prospectively evaluated. Radiotherapy was given by using a three-dimensional conformal technique. Intensity-modulated radiation therapy (IMRT) was used in only a few challenging cases. A median total physical dose of 70 Gy (range, 44~87.9 Gy) was delivered with 2.0~2.9 Gy daily fractions over 4~7 weeks using 6~16 MV photons. Circulating cytokine levels were measured before and at weeks 2 and 4 during RT. All patients were prospectively evaluated weekly during RT, with follow-up evaluation after completion of RT. At each follow-up, patients underwent a history review and physical examination as well as a chest computed tomography scan. The primary endpoint was symptomatic RILT, and higher radiation pneumonitis or symptomatic pulmonary fibrosis. Logistic regression was performed to evaluate the risk factors of RILT. The area under the curve (AUC) for the Receiver Operating Characteristic (ROC) curves were used for model assessment. Results75 patients with stage Ⅰ-Ⅲ NSCLC were included in this study, and 86% patients with RILT after receiving definitive conventionally fractionated radiotherapy. 16 of 65 patients (24.6%) developed RILT2. Lower pre-IL-8 and higher TGF-β1 2 W/pre ratio were associated with a higher risk of RILT2. 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 2 W/pre ratio were included in the final predictive model. Receiver operating characteristic (ROC) curves were evaluated for MLD, baseline IL-8 level, TGF-β1 2 W/pre ratio. The AUC was 0.61 (0.45, 0.77), 0.70 (0.56, 0.84) and 0.68 (0.53, 0.83) with MLD, baseline IL-8 level and TGF-β1 2 W/pre ratio, respectively. The AUC increased to 0.73 by combining MLD, pre-IL-8 and TGF-β1 2 W/pre ratio compared with 0.61 by MLD alone to predict RILT. ConclusionsThis study validated the predictive value of IL-8 and TGF-β1 for RILT. Pre IL-8 level and TGF-β1 2 W/pre ratio provided a more accurate model to predict the risk of RILT2 compared to MLD alone.