Project 1: Understanding normal tissue toxicity to identify patients most likely to benefit from proton therapy.

项目1 -项目概要 质子束治疗与常规治疗相比的潜在益处是预期的 如果仅根据剂量分布（即物理参数）进行判断， 质子和光子之间的生物学差异目前只被认为是 将恒定的加权因子应用于质子剂量，即质子相对生物剂量， 有效性（RBE）为1.1。迫切需要进行更多的研究， 风险器官内剂量和RBE的空间变化是否可以解释不良反应 治疗结果。 质子与光子照射对正常组织毒性的电位差 只能通过具有大量临床数据的研究进行评估，因为 放射治疗中大多数明显毒性的频率较低，因此导致 通常在患者特定放射敏感性的噪声内。存在显著 我们两家机构提供的大量临床数据以及同样重要的专业知识 在基于血液、成像和剂量生物标志物的毒性评估中。 我们假设，在正常组织毒性中， 质子和光子辐射不仅由于剂量分布的差异， 正常组织毒性的RBE变化，目前对此了解甚少。我们 目的是1）了解质子和质子之间正常组织毒性的差异， 光子通过评估剂量反应关系，2）识别生物标志物，以告知 相对正常组织并发症概率，以取代简单的RBE概念，以及3） 通过识别患者， 将受益。 最终，我们的方法将导致新的结果建模概念适用于 质子和光子治疗。

PROJECT 1 - PROJECT SUMMARY A potential benefit of proton beam therapy compared to conventional therapy is expected for many treatment sites if solely judged by the dose distribution, i.e. physical parameters. Biological differences between protons and photons are currently only considered by applying a constant weighting factor to proton doses, i.e. a proton relative biological effectiveness (RBE) of 1.1. There is an urgent need for additional research to examine whether spatial variations in dose and RBE within organs at risk can explain adverse treatment outcomes. The potential difference in normal tissue toxicity between proton and photon irradiation can only be assessed with studies with a substantial amount of clinical data because the frequencies of most overt toxicities in radiation therapy is low, thus causing variations to be typically within the noise of patient specific radiosensitivity. There is a significant amount of clinical data available at our two institutions and equally as important, expertise in assessment of toxicities based on blood, imaging and dosimetric biomarkers. We hypothesize that there are fundamental differences in normal tissue toxicities between proton and photon radiation due not only to differences in the distribution of dose but also variations in RBE for normal tissue toxicities, which are currently poorly understood. We aim to 1) understand the differences in normal tissue toxicities between protons and photons by assessing dose response relationships, 2) identify biomarkers to inform relative normal tissue complication probabilities to replace simple RBE concepts, and 3) advance precision medicine concepts to proton radiotherapy by identifying patients that will benefit. Ultimately our approach will lead to novel outcome modeling concepts applicable to both proton and photon therapy.