De Jaeger Katrien, Seppenwoolde Yvette, Kampinga Harm H, Boersma Liesbeth J, Belderbos José S A, Lebesque Joos V
Department of Radiotherapy, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Int J Radiat Oncol Biol Phys. 2004 Apr 1;58(5):1378-87. doi: 10.1016/j.ijrobp.2003.09.078.
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-beta1 (TGF-beta1) has been reported to be associated with the incidence of RP. It has been proposed that serial measurements of plasma TGF-beta1 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-beta1 levels in patients irradiated for NSCLC in relation to the development of RP and dose-volume parameters.
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-beta1 levels were determined using a bioassay on the basis of TGF-beta1-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-beta1 level, MLD) were associated with the incidence of RP. To improve our understanding of the time course of TGF-beta1 levels, we performed a multivariate analysis to investigate which factors (pre-RT TGF-beta1 level, MLD, RP) were independently associated with the posttreatment TGF-beta1 levels.
The pre-RT TGF-beta1 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-beta1 levels normalized toward the end of treatment and remained stable until 18 weeks after RT. In 29 patients, however, TGF-beta1 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-beta1 level at the end of RT was significantly associated with the MLD (p <0.001) and pre-RT TGF-beta1 level (p = 0.001).
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-beta1 at the end of RT are an independent additional risk factor for developing symptomatic RP. However, the TGF-beta1 level at the end of a RT was significantly associated with the MLD and the pre-RT level.
在非小细胞肺癌（NSCLC）放射治疗（RT）的剂量递增研究中，放射性肺炎（RP）是最重要的剂量限制并发症。据报道，转化生长因子-β1（TGF-β1）与RP的发生率相关。有人提出，连续测量血浆TGF-β1对于评估RP风险以及决定是否可以安全地进行额外的剂量递增可能有价值。本研究的目的是前瞻性评估接受NSCLC放疗患者的TGF-β1水平随时间的变化过程，及其与RP发生和剂量体积参数的关系。
在68例因医学上无法手术或局部晚期NSCLC接受放疗的患者中（剂量范围60.8 - 94.5 Gy），在放疗开始前以及放疗开始后4、6和18周采集血浆样本。使用基于TGF-β1诱导水貂肺细胞中纤溶酶原激活物抑制剂-1表达的生物测定法测定血浆TGF-β1水平。所有患者在放疗前均接受胸部计算机断层扫描（CT），并在放疗后18周重复进行。利用CT数据计算平均肺剂量（MLD）并对放射性影像学改变进行评分。RP根据影像学改变或临床症状的存在来定义。有症状的RP根据常见毒性标准（1级或更严重）和西南肿瘤协作组标准（2级或更严重）进行评分。进行多变量分析以研究哪些因素（治疗前或治疗后TGF-β1水平、MLD）与RP的发生率相关。为了更好地理解TGF-β1水平随时间的变化过程，我们进行了多变量分析，以研究哪些因素（放疗前TGF-β1水平、MLD、RP）与治疗后TGF-β1水平独立相关。
与健康个体（范围4 - 12 ng/mL）相比，NSCLC患者放疗前的TGF-β1水平升高（中位数21 ng/mL，范围5 - 103 ng/mL）。平均而言，TGF-β1水平在治疗结束时恢复正常，并在放疗后18周保持稳定。然而，在29例患者中，放疗结束时TGF-β1相对于放疗前的值升高。多变量分析显示，MLD是与影像学RP风险（p = 0.05）和有症状RP均显著相关的唯一变量，与所使用的评分系统无关（西南肿瘤协作组和常见毒性标准系统分别为p = 0.05和0.03）。放疗结束时的TGF-β1水平与MLD（p <0.001）和放疗前TGF-β1水平（p = 0.001）显著相关。
MLD与影像学和有症状RP的发生率均显著相关。我们的研究结果未证实放疗结束时TGF-β1水平升高是发生有症状RP的独立额外危险因素的报道。然而，放疗结束时的TGF-β1水平与MLD和放疗前水平显著相关。
