创建“可变化肺癌临床靶区”新概念改进ICRU62号报告

The method of optimal target volume delineation for lung cancer patients continues to be a disputable topic due to organ motion associated with respiratory breathing. The microscopic disease (MD) around GTV could neither be imaged nor displayed simultaneously in the CT images, and the ITV obtained from the existing four-dimensional imaging technology is actually the motion trajectory of the GTV. Although the tumor and the MD always move dynamically during delivery and appear in different positions inside the ITV according to the different respiratory phase, the targets are regarded as static treatment volumes and independent on geometric volume. Our previous studies found that the combined use of 4DCT and 3DCT can minimize the uncertainties of ITV delineation for early stage lung cancer. At present, there is no report about the incident rate of the MD inside the ITV as well as its effect on MD dosimetry during irradiation period in the world. In addition, the target edge dose (TED) of the internal target volume (ITV) delivers some incidental irradiation dose (IID) to the MD, which may play a certain role in the control of MD. In order to incorporate incident rate of variable MD inside the ITV and TED, we propose a novel concept of "the variable clinical target volume in lung cancer" to redefine the standard of the individualized clinical target volume. To validate that this concept is suitable for the contouring of the motion target of the lung cancer, we will establish the mathematical models, conduct the phantom experiments, and carry out the clinical trials sequentially. Finally, we anticipate that this proposed study will provide a systematic approach to determine the margins required for V-CTV, and minimize the uncertainties of the lung cancer target volume delineation. As a result, the clinical efficacy of lung SBRT will be improved. Moreover, some concepts used for the definition of target volume in the ICRU reports 62 will be modified to provide radiation oncologists with a more practical and accurate target contouring guideline for the management of lung cancers.

由呼吸运动导致的肺癌靶区最优勾画标准一直饱受争议。现有影像技术无法显示肿瘤周围的显微病灶（MD），通过4D影像获得的ITV是GTV边界的运动轨迹。照射中MD和肿瘤不停的运动并随不同呼吸时相出现在ITV的不同位置，靶区却被视为静态的相互独立的几何体。本课题申请者前期研究发现联合使用4DCT和3DCT可最小化早期肺癌ITV的不确定性，但放疗中MD进入或移出ITV的概率及由此造成的剂量学变化结果国内外尚无报道。此外，ITV靶区边缘剂量（TED）对MD产生的不经意照射剂量（IID）对MD控制也有一定作用。本课题组据此创建"可变化肺癌临床靶区（V-CTV）"新概念，拟通过建立数学模型、模体实验和临床试验，测定MD进入或移出ITV概率和TED及MD受到的IID，从而确定V-CTV外扩标准，改善早期肺癌SBRT的增益比，改进ICRU62号报告的不足，为临床医生提供更实用、准确的肺癌靶区勾画指南。

呼吸运动使得肺癌靶区勾画标准一直存在争议。本课题组对纳入的早期非小细胞肺癌患者行4DCT定位扫描，确定ITV，采集肿瘤运动参数，发现在早期肺癌行SBRT治疗期间，肿瘤体积有缩小，约30%患者放疗前后瘤体缩小超过5mm，尤其以前后方向瘤体变化最为明显；当放疗生物等效剂量达到60Gy时，我们对瘤体变化超过25%患者修订靶区，校正放疗计划，结果显示可以有效减少瘤体漏照的发生率，明显减轻对危及器官的过度照射；.通过模拟自由呼吸状态下肺部肿瘤放疗分次内位移变化，构建数学模型，计算显微病灶MD进入及移出ITV的概率，并结合4DCT的静态剂量分布，计算出显微病灶理论计算值。运用模拟呼吸运动模体和光释光进行实验，实测运动状态下MD剂量分布，与MD理论计算值比较，发现周期运动靶区的MD理论计算值与光释光实测值差别在5%以内，说明本概率模型可以准确预测周期运动靶区MD受量，而且研究显示距离ITV10mm以内的区域接受了＞80Gy的生物剂量，表明呼吸运动使得MD接受不经意照射剂量增加，无需外扩CTV边界就能够保证GTV和MD的受照射剂量；采用常规静态的剂量计算方式并不能准确反映MD的实际受照射剂量。.依据所建概率模型、模体实验的结果，通过临床试验，在早期肺癌SBRT分次治疗期间，对肿瘤体积变化较大患者及时修订靶区和放疗计划，其余患者按最初计划治疗，由于临床随访周期较长，目前SBRT患者局部控制率、无进展生存率、远处转移率、总生存率等后续工作正在进行中。初步分析发现治疗相关毒副反应以呼吸系统并发症多见。.总之，本课题组所构建的显微病灶MD进入及移出ITV的概率模型能够准确预测周期运动靶区MD受量，早期肺癌SBRT过程中及时修订瘤体变化幅度大患者的照射靶区和放疗计划可以改善了早期肺癌SBRT治疗的增益比。