Dose painting based on hypoxia and proliferative response

描述(由申请人提供)： 癌症治疗的下一个重大进展将发生在范式从以人群为基础转向以患者为基础的个性化剂量处方的过程中。在放射治疗中，这一范式的转变不仅需要调整处方的总剂量，而且还需要从目前的统一剂量处方标准转变为非统一剂量处方，这将根据肿瘤生物学特性的空间分布而量身定做--这一过程通常被称为“剂量绘制”。为了确保对人类患者的安全移植，我们建议对犬自发性鼻部肿瘤模型进行彻底的研究。将考虑四个治疗组：(1)标准放疗，(2)均匀剂量递增，(3)基于缺氧的非均匀剂量递增，(4)基于增殖反应的非均匀剂量递增。将进行PET/CT成像，以指导治疗剂量处方和评估治疗反应。Flt-PET作为细胞增殖的替代物，CuATSM-PET作为肿瘤缺氧的替代物，FDG-PET作为肿瘤代谢的替代物。通过对放射治疗开始前采集的组织活检样本进行广泛的IHC评估，将确定与生物替代品的相关性。总体假设是，基于生物成像(剂量绘制)的非均匀剂量递增导致比均匀剂量递增更有效的放射治疗，从而提供相同的整体剂量增加。这一假设将在三个特定目标中进行检验：具体目标1：比较均匀剂量递增与标准治疗的具体目标2：比较基于缺氧的非均匀剂量递增(基于缺氧的剂量绘制)与基于均匀剂量递增的具体目标3：比较基于增殖反应(基于增殖反应的剂量绘制)的非均匀剂量递增与一致剂量递增。此外，我们还将进行三项辅助研究：辅助研究1：将早期增殖反应与治疗反应相关联辅助研究2：将早期增殖反应与复氧相关。辅助研究3：早期增殖反应与肿瘤复发部位的空间相关性。与公共卫生相关：个体化放射治疗是放射治疗发展的下一个合乎逻辑的步骤，其中辐射剂量将根据个体患者的肿瘤生物学特征进行定制。这种方法将彻底改变放射治疗的处方和计划方式，并将在局部肿瘤控制和对未受影响组织的副作用方面改善治疗结果。

DESCRIPTION (provided by applicant): The next significant advance in cancer therapy will occur with the paradigm shift from a population-based to a personalized patient-based dose prescription. In radiation therapy this paradigm shift will require, not only adjustment of the total dose prescribed, but also a shift from the current standard of uniform dose prescription to a non-uniform dose prescription, which will be tailored to the spatial distribution of biological properties in the tumor - the process most often termed "dose-painting". To ensure safe translation to human patients, we propose a thorough investigation on a canine spontaneous nasal tumor model. Four treatment groups will be considered: (1) Standard radiotherapy, (2) Uniform dose escalation, (3) Non- uniform dose escalation based on hypoxia and (4) Non-uniform dose escalation based on proliferative response. PET/CT imaging will be performed to guide treatment dose prescription and evaluate treatment response. FLT-PET will be used as a surrogate of cell proliferation, CuATSM-PET as a surrogate of tumor hypoxia and FDG-PET as a surrogate of tumor metabolism. Correlation to biological surrogates will be established by performing extensive IHC assessment on a tissue biopsy sample taken prior to the start of radiation therapy. The overall hypothesis is that non-uniform dose escalation based on biological imaging (dose painting) leads to more effective radiotherapy than uniform dose escalation delivering the same integral dose boost. This hypothesis will be tested within three specific aims: Specific Aim 1: To compare uniform dose escalation to standard therapy Specific Aim 2: To compare non-uniform dose escalation based on hypoxia (hypoxia-based dose painting) to uniform dose escalation Specific Aim 3: To compare non-uniform dose escalation based on proliferative response (proliferative response-based dose painting) to uniform dose escalation In addition, we will perform three auxiliary studies: Auxiliary Study 1: To correlate early proliferative response and pre-treatment hypoxia to treatment response Auxiliary Study 2: To correlate early proliferative response to reoxygenation. Auxiliary Study 3: To spatially correlate early proliferative response to the position o tumor recurrence. PUBLIC HEALTH RELEVANCE: Individualized radiotherapy, where radiation dose will be tailored to individual patient tumor biological characteristics, is the next logical step in radiotherapy development. This approach will revolutionize the way that radiotherapy is prescribed and planned, and will improve the therapeutic outcome in terms of local tumor control and side-effects to unaffected tissue.