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

 描述（由申请人提供）：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率：（1）在局部失败风险较高的选定患者中，通过FDG PET/CT引导的肿瘤剂量递增增加局部控制，以及（2）通过避免灌注SPECT/CT上定义的肺功能的放射剂量来限制肺毒性。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%，同时具有很大的毒性风险，在20%的患者中观察到3+格拉德肺毒性。在本提案中，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性肺的辐射剂量更能预测临床毒性，以及对局部失败高风险患者的选择性剂量递增是否能改善肿瘤控制，同时限制毒性。具体目标是：（1）评价功能性肺回避和反应适应性升级（FLARE）RT在局部晚期NSCLC患者队列中的毒性;（2）将基线灌注成像参数与治疗后放射性肺炎相关联;以及（3）根据局部RT剂量诱导的灌注成像参数变化预测肺功能测试的变化。为了支持上述目标，接受RT的局部晚期NSCLC患者将在基线、RT第3周和RT后3个月期间接受肺功能检查（PFT）和灌注/通气SPECT/CT和PET/CT。将通过结合差异避免计划来实施高精度放射治疗，以减少SPECT/CT定义的灌注肺的平均剂量，以及在被归类为早期FDG PET无应答者的选定患者中，在3周治疗中期FDG PET/CT上定义的差异肿瘤剂量递增。将SPECT/CT灌注图像直方图和肺功能异质性的纹理特征与基于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建模为剂量阈值以上功能完全丧失的二分剂量反应、每个剂量箱中功能部分丧失的分箱剂量反应和体素尺度下的连续剂量反应。该项目将联合收割机功能性肺避免和选择性剂量递增精确地结合在一种创新方法中，可以使患有局部晚期肺癌的异质性患者人群的每个部分受益。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，该试验有可能显著改善局部晚期NSCLC患者的结局。

 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.