代谢与增殖显像指导非小细胞肺癌个体化放疗靶区剂量雕刻的分子机制及应用研究

The introduction of individual treatment into clinical practice is of great importance because it gives us the chance to improve tumor cure rates by treatment intensification in patients who are likely to respond while preventing the use of ineffective therapies with the associated normal tissue toxicity. The key of improving the effective of radiotherapy in non-small cell lung cancer (NSCLC) is to make sure the biological characteristics, such as metebolic and proliferation. For this, reliable predictive biologically rational markers are required that guide radiation oncologists to optimal dose presscription, selection of fraction schemes and of combined treatment for each individual patients. Detecting metabolic and proliferation using tumor tissue obtained via a biopsy or surgical resection is now routinely uesd. Because a biopsy is an invasive procedure, it is desirable to replace it with a noninvasive procedure.The encouraging improvements of anticancer treatments, better understanding of biological mechanisms of tumor resistance to therapies including radiation along with the rapid development of molecular imaging have necessitated the development of biomarkers to predict a group of patients with maximal benefit from specific treatment. Because of the heterogeneous distribution of 18F-FDG or 18F-FLT uptake within the tumor, one approach to utilize 18F-FDG or 18F-FLT PET for specific treatment is to apply inhomogeneous radiation doses to the tumor, i.e. tumor regions with elevated 18F-FDG avidity are irradiated with higher doses and standard or reduced doses are delivered to the rest of the tumor. The biological rationale for this strategy is that high 18F-FDG or 18F-FLT uptake reflects tumor regions with high cell density or proliferation, respectively. However, there is no evidence yet on the use of 18F-FDG or 18F-FLT PET imaging for this selection of patient for individualized radiotherapy. Therefore, the aim of this study is to detect whether 18F-FDG or 18F-FLT uptake could really reflect tumor regions with high cell density or proliferation, resepctively, and to detect when to conduct PET scan is the best to reflect tuomor metabolic or proliferation during radiotherapy. Then with the considerable progress in non-invasive functional and molecular imaging, the tools for treatment individualization based not only on morphological criteria but also on biological information such as metabolic and proliferative actively before and during treatment are becoming available. Development, validation and integration of imaging biomarkers using PET to improve radiotherapy are therefore an important task for further clinical practice.

提高NSCLC放疗疗效的关键在于对患者分子生物特征的个体化研究，在肿瘤解剖靶区基础上考虑代谢、增殖等与放疗相关的生物学特性，选择个体化雕刻剂量及分割方式。目前检测肿瘤代谢与增殖的手段多为有创性、不易重复获取、不能全面评价代谢与增殖状态。功能分子影像技术可能是无创性动态检测肿瘤代谢与增殖的理想方法，然而FDG和FLT摄取区能否真实反映以及放疗中何时能准确反映肿瘤细胞的代谢和增殖信息，有待深入研究证实。本课题组拟在前期工作基础上，通过代谢和增殖显像结合数字化病理大切片为技术手段，分别验证PET/CT图像上FDG和FLT摄取区与在体肿瘤组织代谢和增殖活性区域空间位置的一致性，从而获得代谢和增殖显像指导NSCLC个体化放疗生物亚靶区剂量雕刻的理论基础；并进一步明确最佳显像时间点,优化代谢和增殖显像引导NSCLC放疗过程中的生物靶区勾画和局部加量，从而有望实现真正意义上个体化放疗靶区的剂量雕刻。

项目背景：NSCLC放疗失败的主要原因是群体化的放疗不适合存在个体差异的患者。基于肿瘤生物特性如代谢、增殖等的靶区勾画及剂量雕刻成为关键。.主要研究内容：（1）NSCLC患者肿瘤组织18F-FDG和18F-FLT摄取区与在体肿瘤组织代谢和增殖活性区空间位置的吻合度。（2）结合FDG和FLT双示踪剂PET/CT，指导肿瘤代谢和增殖靶区勾画和局部加量。（3）验证肿瘤增殖和加速再增殖病理图像与18F-FLT PET显像的空间一致性，指导剂量雕刻。（4）肺癌放疗过程中评价肿瘤再增殖18F-FLT摄取、CT值、肿瘤体积。.重要结果和关键数据：（1）12名患者原发灶SUVmax为3.26±0.97 （range, 1.96-5.05），Ki-67指数最大值49.6%±7.9% （range,5%-90%）。（2）23名患者FDG-SUVmax7.23，FLT-SUVmax3.33，P<0.001。原发灶FDG-SUVmax8.58，FLT-SUVmax3.88，P<0.001。（3）相较未放疗组，SUVmax在3f/6d组降低（P=0.000），6f/12d组SUVmax较3f/6d组增高（P=0.000），较未放疗组无变化（P=0.056）；随着放疗次数增加SUVmax逐渐降低。在未放疗组，Ki-67增殖指数79.82%，3f/6d组为78.47%，6f/12d组达到82.33%，P=0.06；12f/24d和18f/36d组下降（Ps=0.000）。（4）12Gy/6f和6Gy/3f组Ki-67指数升高（P<0.0001,P=0.002）。36Gy/18f组肿瘤体积为（828.76±76.72）mm3，36Gy/18f组为（830.83±102.77）mm3。与非放疗组肿瘤相比12Gy/6f组SUVmax、SUVmean和T/NT比值增加（2.527，Psuvmax＜0.001，1.614，PSUVmean＜0.001；4.250，PT／NT=0.001）和6Gy/3f/6d组（2.494，PSUVmax=0.001；1.300，Psuvmean=0.027；4.750,PT/NT=0.002）。.科学意义：应用代谢和增殖显像指导NSCLC个体化放疗靶区剂量雕刻；优化代谢和增殖显像引导NSCLC放疗过程中的生物靶区勾画和局部加量，为实现真正意义个体化放疗提供理论依据。