分子影像（FDG-PET/CT）为基础的局部晚期非小细胞肺癌个体化精确放射治疗研究

Lung cancer is the leading cause of cancer death in the worldwide. The majority of these patients are inoperable or unresectable at the time of diagnosis, due to the presence of locally advanced disease (40%), distant metastases (40%), or co-morbid conditions. Radiation therapy is the principal mode of treatment for medically inoperable patients with early stage disease and important local treatment for unresectable locally advanced disease. Despite advances in radiation technology, treatment outcomes remain poor, and local tumor failure remains a major problem after radiation-based non-surgical treatment. Local tumor control correlates with overall survival. Radiation treatment dose is an important factor for local tumor control and survival in non-small cell lung cancer (NSCLC). Primary Hypothesis of this trial: Individualized adaptive radiation treatment based on a during-treatment PET/CT scan can deliver a higher total dose to the residual active tumor in the vast majority of patients while keeping the dose to adjacent normal structures unchanged or decreased. Primary Objectives: 1) Compared to conventional RT without adaptive planning, this during-treatment PET/CT based individualized treatment will provide an improvement in the local-regional tumor control without increasing the risk of normal tissue complications in patients with locally advanced NSCLC. 2) The maximum intensity of FDG uptake at baseline and mid-treatment and the reduction in intensity of FDG uptake and in total volume of FDG avid disease from baseline to mid-treatment PET/CT will predict the likelihood of local-regional control from chemoradiation and survival. 3) To determine whether a model of combining current clinical or physical dosimetric factors and biomarkers pre- or during-RT can predict long-term, local-regional tumor control and grade ≥ 3 adverse events better than the current models using clinical factors alone using clinical factors alone. The proposed study would be the first trial from our country, to provide personalized radiation therapy to each patient based on functional imaging acquired during the course of treatment. This approach will allow use of image guided radiation therapy (IGRT) to target the metabolically active tumor while sparing normal functioning tissue to individualize the radiation dose prescription/escalation for the maximized therapeutic gain. This is innovative, as it also aims to evaluate functional imaging during the course of treatment to predict the outcome of a completed course of treatment. The study also should fill the gap in the evidence on predictive models using functional image and molecular markers prior to or during the course of treatment. If successful and further confirmed by a phase III study, this approach will develop a new paradigm of individualized radiation therapy through a careful application of modern radiation technologies.

根据功能分子影像学特点设计个体化放疗计划，结合生物学标记物行放疗疗效及毒副反应预测是目前肿瘤放射治疗研究的方向之一。我们前期针对局部晚期非小细胞肺癌的小样本研究发现：根据FDG-PET/CT 的影像学特点行个体化放疗，放疗剂量从60Gy 递增至74Gy以上是安全可行的，并且显著延长患者生存。然而，目前对此尚无可信的随机对照研究，对疗效和毒副反应也缺乏有效的预测手段。本课题将在前期研究的基础上行随机对照研究，明确：1）根据FDG-PET/CT分子影像学改变行个体化放疗剂量递增的可行性；2）生物学标记物 如OPN、CEA、CYFRA21-1、IL-6等在预测肿瘤治疗疗效中的作用；3）放疗剂量学参数 MLD 联合生物学标记物 TGFβ1、IL-8 在评价放射性肺损伤中的意义。本课题的完成不但可形成一个新的放疗策略，而且将以患者功能分子影像及生物学标记为基础建立放疗疗效预测模型和毒副反应预测模型。

根据功能分子影像学特点设计个体化放疗计划，结合生物学标记物行放疗疗效及毒副反应预测是目前肿瘤放射治疗研究的热点之一。前期小样本的研究提示，根据FDG-PET/CT 的影像学特点对局部晚期非小细胞肺癌行个体化放疗，放疗剂量从60Gy 递增至74Gy 是安全可行的，并且显著延长患者生存。然而，目前对此尚无可信的随机对照研究结果，对疗效和毒副反应也缺乏有效的预测手段。本课题旨在针对局部晚期非小细胞肺癌，通过随机对照研究，明确：1）根据FDG-PET/CT 分子影像学改变对局部晚期非小细胞肺癌行个体化放疗剂量递增的可行性；2）生物学标记物 如OPN、CEA、CYFRA21-1、IL-6 等在预测肿瘤治疗疗效中的作用；3）放疗剂量学参数 MLD 联合生物学标记物 TGFβ 1、IL-8 在评价放射性肺损伤中的意义。课题组成员首先进行了运用18F-FDG-PET/CT成像技术在指导非小细胞肺癌生物适形调强放射治疗中的可行性及其价值的研究。研究结果提示：在接受根治性放射治疗患者中，PET/CT使 60%的患者因靶区发生改变而需要重新设计放射治疗计划。根据18F-FDG-PET/CT融合图像与根据单纯CT图像所设计的放疗计划中的GTV、及肺的V20和MLD之间的差异均有显著统计学意义( P均<0.01) ,18F-FDG-PET/CT融合图像组小于单纯CT图像组，提示根据PET/CT融合图像勾画靶区进行计划设计有可能提高放疗的肿瘤局部控制率及减轻对肿瘤周围组织的放射相关性损伤；而且，根据PET/CT融合图像勾画靶区，不同研究者所勾画的靶区的差异性明显缩小。第二，本项目发现，根据FDG-PET/CT 分子影像学改变行个体化放疗剂量递增，患者毒副反应可耐受、肿瘤治疗客观有效率明显提高（P<0.05）。由于受1年项目计划时间的限制，目前尚未完成50例患者的随机对照入组，故对“生物学标记物 如OPN、CEA、CYFRA21-1、IL-6 等在预测肿瘤治疗疗效中的作用”以及“放疗剂量学参数 MLD 联合生物学标记物 TGFβ 1、IL-8 在评价放射性肺损伤中的意义”的研究，目前数据尚在继续积累和统计中。本课题的完成不但可能形成一个新的放疗策略，而且将有可能以患者功能分子影像及生物学标记为基础建立放疗疗效预测模型和毒副反应预测模型。