Personalized radiation therapy through functional lung avoidance and response-adaptive dose escalation: utilizing multimodal molecular imaging to improve the therapeutic ratio

 描述(申请人提供)：我们建议为局部晚期NSCLC患者提供个性化放射治疗，通过以下方式提高治疗比率：(1)通过FDG PET/CT引导的肿瘤剂量递增来提高局部控制率，以及(2)通过避免局部失败的辐射剂量来限制肺毒性，以及(2)通过SPECT/CT灌注成像定义的肺功能来限制肺毒性。RT是局部晚期非小细胞肺癌(NSCLC)患者的主要治疗选择，但目前的治疗导致肿瘤控制不佳，局部失败率高达50%，同时存在相当大的毒性风险，20%的患者出现3级以上肺部毒性。在这项提案中，我们将探讨以下基本问题：功能性肺的辐射剂量是否比解剖肺的辐射剂量更好地预测临床毒性，以及局部失败风险高的患者的选择性剂量递增是否在限制毒性的同时改善肿瘤控制。具体目的是：(1)评估局部晚期非小细胞肺癌患者队列中功能性肺回避和反应适应性升级(FLARE)放疗的毒性；(2)将基线灌注成像参数与治疗后放射性肺炎相关；(3)根据局部放疗剂量引起的灌注成像参数的变化来预测肺功能测试的变化。为了支持上述目标，接受放疗的局部晚期非小细胞肺癌患者将在放疗前、放疗3周和放疗后3个月进行肺功能测试(PFT)和灌注/换气SPECT/CT和PET/CT。高精度放射治疗将结合差异化避免计划，以减少SPECT/CT定义的灌注肺的平均剂量，以及在选定的被归类为早期FDG PET无反应的患者中，在3周中期FDG PET/CT定义的不同肿瘤剂量递增。SPECT/CT灌注图像直方图和肺功能异质性的纹理特征将与基于CT的剂量-体积参数进行比较，以确定与肺毒性的相关性。SPECT/CT灌注图像摄取的空间映射变化将被模拟为在剂量阈值以上完全丧失功能的二分式剂量反应，在每个剂量盒中部分丧失功能的二分式剂量反应，以及在体素尺度上的连续剂量反应。该项目将以一种创新的方法将功能性肺避免和选择性剂量递增精确地结合在一起，使患有局部晚期肺癌的异质患者群体的每一部分都受益。FLARE RT的成功完成将为在II/III期多中心试验中评估FLARE RT的疗效铺平道路，有可能显著改善局部晚期NSCLC患者的预后。

 DESCRIPTION (provided by applicant): We propose to deliver personalized radiation therapy to patients with locally advanced NSCLC that improves the therapeutic ratio by: (1) increasing local control through FDG PET/CT-guided tumor dose escalation in select patients at high risk of local failure, and (2) limiting pulmonary toxicity through radiation dose avoidance of functiona lung defined on perfusion SPECT/CT. RT is a major treatment option for patients with locally advanced non-small cell lung cancer (NSCLC), but current treatments result in suboptimal tumor control with local failures up to 50%, while carrying substantial risk of toxicity, with grad 3+ pulmonary toxicity seen in 20% of patients. In this proposal, we will explore the fundamental questions of whether radiation dose to functional lung better predicts clinical toxicity than radiation dose to anatomic lung, and whether selective dose escalation to patients at high risk of local failure improves tumor control, while limiting toxicity. The specific aims are: (1) to evaluae toxicity of Functional Lung Avoidance & Response-adaptive Escalation (FLARE) RT in a cohort of locally advanced NSCLC patients; (2) to correlate baseline perfusion imaging parameters with post-treatment radiation pneumonitis; and (3) to predict changes in pulmonary function tests from regional RT dose-induced changes in perfusion imaging parameters. In support of the above aims, patients with locally advanced NSCLC receiving RT will undergo pulmonary function tests (PFTs) and perfusion/ventilation SPECT/CT and PET/CT at baseline, during week 3 of RT and 3 months post-RT. High precision radiation therapy will be administered by combining differential avoidance planning to reduce mean dose to SPECT/CT-defined perfused lung, and differential tumor dose escalation defined on 3 week mid-treatment FDG PET/CT in select patients classified as early FDG PET non-responders. SPECT/CT perfusion image histogram and textural features of lung function heterogeneity will be compared against CT-based dose-volume parameters for correlation to pulmonary toxicity. Spatially mapped changes in SPECT/CT perfusion image uptake will be modeled as a dichotomous dose-response with complete loss of function above dose thresholds, a binned dose-response with partial loss of function in each dose bin, and continuous dose-response at the voxel scale. This project will precisely combine functional lung avoidance and selective dose escalation in an innovative approach that can benefit each segment of a heterogeneous patient population with locally advanced lung cancer. Successful completion will pave the way for efficacy evaluation of FLARE RT in a phase II / III multi-center trial with the potential to significantly improve outcome of patients with locally advanced NSCLC.