功能分子影像指导局部晚期非小细胞肺癌自适应放射治疗研究

Radiation therapy is the principal mode of treatment for locally advanced non-small cell lung cancer (NSCLC). 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 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) The post-operative pathology results will confirm that this during-treatment PET/CT based individualized treatment in patients with locally advanced NSCLC is feasible. 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. 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, this approach will develop a new paradigm of individualized radiation therapy through a careful application of modern radiation technologies.

根据肿瘤治疗不同阶段功能分子影像学的改变特点设计个体化自适应放疗计划，并结合患者外周血分子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的研究方向之一。我们前期针对局部晚期非小细胞肺癌的小样本研究发现：根据放疗过程中FDG-PET/CT 的影像学改变行自适应放疗，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，目前尚无可信的研究证实根据PET/CT指导肿瘤自适应放疗的准确性，对放疗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）根据疗程中FDG-PET/CT功能分子影像学改变行个体化自适应放疗的可行性；2）功能分子影像结合分子生物学标记物在预测肿瘤放疗疗效及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射治疗策略，而且将以患者功能分子影像及分子生物学标记物为基础建立放疗疗效预测和毒副反应预测模型。

根据肿瘤治疗不同阶段功能分子影像学的改变特点设计个体化自适应放疗计划，并结合患者外周血分子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的热点之一。前期小样本研究发现：根据 FDG-PET/CT 的影像学特点对局部晚期非小细胞肺癌行自适应放疗，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，目前尚无可信的随机对照研究证实 PET/CT 指导肿瘤自适应放疗的准确性，对放疗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）根据疗程中 FDG-PET/CT 功能分子影像学改变行个体化自适应放疗的可行性；2）功能分子影像结合分子生物学标记物在预测肿瘤放疗疗效及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成像指导下的缩野加量自适应放射治疗在不可手术局部晚期非小细胞肺癌中的疗效和安全性研究。研究结果提示：缩野及同步推量放疗组ORR明显大于常规放疗组。缩野组及同步推量放疗组的OS和PFS中位数分别为22.0个月和12.4个月，明显长于常规放疗组(P=0.045，P=0.013)。常规放疗组分别为18.1个月和8.2个月。第二，本项目发现，缩野及同步推量放疗组与常规放疗组在放射剂量参数和危险器官（OAR）方面无显著性差异。两组间2级或以上的放射性肺损伤、放射性食管炎、放射性心肌损害和骨髓抑制的发生率均无统计学差异。目前血液采集已完成，TGFβ 1、IL-8、OPN、CEA、CYFRA21-1、IL-6等生物标记物已送检，结果整理中，待统计结果再进行与临床疗效及放射性肺损伤的相关性研究。放疗疗效及放射性肺损伤预测模型正在建立中。本课题的研究结果提示功能分子影像 PET/CT 引导下的局部晚期非小细胞肺癌自适应放射治疗在实际操作中是安全可行的，能提高患者 ORR，延长 OS 和 PFS，同时明显不增加放射性毒副反应发生率。课题的完成不但可形成一个新的放射治疗策略，而且将以患者功能分子影像及分子生物学标记物为基础建立放疗疗效预测和毒副反应预测模型。

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