功能分子影像指导非小细胞肺癌个体化放疗研究

The fact that the standard radiotherapy could not match every individual tumor variation is the main cause of local failor in patients with non-small cell lung cancer (NSCLC). The individualized radiotherapy based on personal unique features is the way to the success. Molecular imaging may be the best tool to get the dynamic and spatial biology features safely. Prior researches indicated that genetic variation, glucose metabolism and angiogenesis were correlated with outcome of radiotherapy but their imaging were not studied and applied to radiotherapy deeply. This study is designed to build the individualized radiotherapy technique step by step with animal transplantation tumor and clinical research. First, the accuracy of genetic variation, FDG PET imaging for glucose metabolism and RGD PET imaging for angiogenesis will be identified by imaging-specimen-molecular pathology match and compare. Second, a complex prognosis prediction model for radiotherapy will be set up based on molecular imaging and clinical information. Third, individualized molecular imaging will matched with the structure originate from the tumor after radiotherapy point to point and sub-region radiosensitivity predicting model will be set-up in this way, and then the individualized biological target volume can be contoured and the individualized dose can be administered. Finally, an individualized radiotherapy system can be built for patients with NSCLC.

非小细胞肺癌放疗失败的主要原因是基于群体化证据的放疗技术不适合存在巨大差异的肺癌个体。只有充分掌握肺癌个体化特征，实施有针对性的个体化放疗才能提高疗效。分子影像技术可立体、无创、动态显示肺癌的个体化特征，为个体化放疗提供指导。前期研究提示肺癌基因变异、功能代谢和血管生成状态决定的微环境特征与放疗疗效关系密切，但缺乏系统显像研究与应用。本研究拟进行动物和临床研究：1）通过影像-手术标本-分子病理精确对照研究，验证基因表达、FDG PET代谢显像、RGD PET血管生成显像的准确性；2）通过个体化特征多模态功能分子影像、临床因素与放疗疗效的相关性分析，优化筛选，构建放疗疗效综合预测模型，指导个体化治疗策略选择；3）通过个体化特征分子影像纹理与放疗后肿瘤转归做精确匹配的立体相关分析，建立肿瘤内亚区域的放射敏感性精确预测方法，指导个体化生物靶区勾画和个体化剂量施照，建立非小细胞肺癌个体化放疗技术。

按照任务书的计划要求，课题组以肺癌移植瘤小鼠和非小细胞肺癌患者为研究对象，从以下三个方面，逐步完善非小细胞肺癌个体化放疗技术，全面执行了课题计划：（1）应用靶向肿瘤能力的RGD功能多肽，从Lewis小鼠肺癌模型实验到临床验证，证明18F-RGD PET示踪剂的安全性，并通过精确的影像-病理对照研究，确定RGD PET肿瘤新生血管显像在界定肺癌靶区的准确性并将纵膈淋巴结诊断的准确率提高了12.1%。完善FDG PET糖代谢动态显像方法，确定50%SUVmax勾画的体积是适合加量的区域。（2）通过动物实验证明放疗前后RGD PET SUVmax和整合素αvβ3的变化与OS明显相关；开展了个体化特征多模态功能分子影像FDG PET/CT、RGD PET/CT、V/Q SPECT与放疗疗效的相关性分析，证实RGD-PET 肿瘤血管生成显像、FDG PET与NSCLC放化疗敏感性的相关性以及V/Q SPECT与放射性损伤的相关性，结合临床因素，确立了放化疗敏感性和肺损伤的预测模型，并优化筛选出RGD PET在基线水平预测进展期非小细胞肺癌患者肿瘤放化疗敏感性的比较优势，通过前瞻性的临床试验证实其在胶质瘤、食管癌等其他肿瘤也取得了超越传统MRI和FDG PET的优势。（3）通过对RGD PET, FDG PET个体化特征分子影像纹理与放疗后肿瘤转归做精确匹配的立体相关分析，建立肿瘤内亚区域的放射敏感性精确预测和个体化靶区勾画及个体化剂量施照的方法，建立起NSCLC个体化放疗技术，并在全国开展了多中心临床验证。