Craddock Matthew, Nestle Ursula, Koenig Jochem, Schimek-Jasch Tanja, Kremp Stephanie, Lenz Stefan, Banfill Kathryn, Davey Angela, Price Gareth, Salem Ahmed, Faivre-Finn Corinne, van Herk Marcel, McWilliam Alan
Radiotherapy Related Research Group, Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom.
Department of Radiation Oncology, Medical Center, University of Freiburg, Freiburg, Germany; Department of Radiation Oncology, Kliniken Maria Hilf, Mönchengladbach, Germany.
J Thorac Oncol. 2023 Jan;18(1):57-66. doi: 10.1016/j.jtho.2022.09.004. Epub 2022 Sep 18.
Heart dose has emerged as an independent predictor of overall survival in patients with NSCLC treated with radiotherapy. Several studies have identified the base of the heart as a region of enhanced dose sensitivity and a potential target for cardiac sparing. We present a dosimetric analysis of overall survival in the multicenter, randomized PET-Plan trial (NCT00697333) and for the first time include left ventricular ejection fraction (EF) at baseline as a metric of cardiac function.
A total of 205 patients with inoperable stage II or III NSCLC treated with 60 to 72 Gy in 2 Gy fractions were included in this study. A voxel-wise image-based data mining methodology was used to identify anatomical regions where higher dose was significantly associated with worse overall survival. Univariable and multivariable Cox proportional hazards models tested the association of survival with dose to the identified region, established prognostic factors, and baseline cardiac function.
A total of 172 patients remained after processing and censoring for follow-up. At 2-years posttreatment, a highly significant region was identified within the base of the heart (p < 0.005), centered on the origin of the left coronary artery and the region of the atrioventricular node. In multivariable analysis, the number of positron emission tomography-positive nodes (p = 0.02, hazard ratio = 1.13, 95% confidence interval: 1.02-1.25) and mean dose to the cardiac subregion (p = 0.02, hazard ratio = 1.11 Gy, 95% confidence interval: 1.02-1.21) were significantly associated with overall survival. There was a significant interaction between EF and region dose (p = 0.04) for survival, with contrast plots revealing a larger effect of region dose on survival in patients with lower EF values.
This work validates previous image-based data mining studies by revealing a strong association between dose to the base of the heart and overall survival. For the first time, an interaction between baseline cardiac health and heart base dose was identified, potentially suggesting preexisting cardiac dysfunction exacerbates the impact of heart dose on survival.
心脏剂量已成为接受放疗的非小细胞肺癌（NSCLC）患者总生存期的独立预测指标。多项研究已确定心脏底部是剂量敏感性增强的区域，也是心脏保护的潜在靶点。我们对多中心随机PET-Plan试验（NCT00697333）中的总生存期进行了剂量学分析，并首次将基线时的左心室射血分数（EF）作为心脏功能指标纳入分析。
本研究纳入了205例无法手术的II期或III期NSCLC患者，接受60至72 Gy、每次2 Gy的分割放疗。采用基于体素的图像数据挖掘方法，确定高剂量与较差总生存期显著相关的解剖区域。单变量和多变量Cox比例风险模型检验了生存期与已确定区域的剂量、既定预后因素及基线心脏功能之间的关联。
经过处理和随访审查后，共有172例患者留存。在治疗后2年，在心脏底部确定了一个高度显著的区域（p < 0.005），该区域以左冠状动脉起源和房室结区域为中心。在多变量分析中，正电子发射断层扫描阳性淋巴结数量（p = 0.02，风险比 = 1.13，95%置信区间：1.02 - 1.25）和心脏亚区域的平均剂量（p = 0.02，风险比 = 1.11 Gy，95%置信区间：1.02 - 1.21）与总生存期显著相关。EF与区域剂量之间存在显著的生存交互作用（p = 0.04），对比图显示区域剂量对EF值较低患者的生存期影响更大。
本研究通过揭示心脏底部剂量与总生存期之间的强关联，验证了先前基于图像的数据挖掘研究。首次确定了基线心脏健康状况与心脏底部剂量之间的交互作用，这可能表明预先存在的心脏功能障碍会加剧心脏剂量对生存期的影响。
