Improving preclinical proton radiation dosimetry using a biologically relevant murine dosimetry phantom

放射治疗(RT)治疗癌症的目标是向肿瘤提供尽可能多的辐射剂量，同时将向周围正常组织提供的剂量降至最低。质子束疗法(PBT)是放射治疗的另一种形式，它将高能粒子(质子)而不是传统的X射线(光子)传递给肿瘤。质子的有利剂量沉积遵循较低的入射剂量，最终导致陡峭的剂量梯度和快速下降(布拉格峰)，提高了对肿瘤的剂量传递的精确度。由于产生质子所需的总成本和技术，实验通常在临床部门的专用研究室进行，使用专为人类治疗而设计的设备。人类和小鼠之间的巨大尺寸差异使得很难利用小动物体内的布拉格峰值剂量分布，因此通常使用束流的初始平台区域来照射靶子。然而，这意味着射束延伸到靶外，因为射束能量太高，无法被小动物衰减，因此，健康组织受到辐射，增加了毒性。为了提高辐照的精度，并将束流缩小到小动物尺寸，使用了各种跨机构的技术和设备，包括距离移位器、能量降解器、屏蔽或准直器。本研究的目的是采用先前开发的3D打印鼠标形状的工具(体模)来测量质子剂量，使用放射变色胶片来确保在小动物尺度上准确的质子剂量传输。我们的目标是通过测量水凝胶珠包裹的3D肿瘤细胞基质中的DNA损伤来验证这一点。随后，作为剂量测量审计的一部分，该模型将被交付给多个国际机构，测试所使用的技术，并比较计划和提供的剂量。这将通过我们与Inspire项目和粒子治疗合作小组(PTCOG)的现有合作来促进。目前，一小部分动物(约200只)被用于初步研究，以测试不同设备的适用性，以减小光束大小以适应特定的实验。通过多中心审核，我们的目标是向直接用户展示，我们开发的体模可以成为这些动物的合适替代品。该模型还可以作为老鼠的替代品，以改进实验和简化设置，减少动物处于麻醉或固定状态的时间。根据一项文献搜索，在过去的5年里，大约有1300只小鼠被用于质子研究，但随着质子束技术变得更加广泛，这个数字将会上升。定期使用该工具来测量剂量输出并发现任何问题将增加对结果的信心，从而减少获得具有统计意义的数据所需的动物数量，并改进剂量传递以将潜在毒性降至最低。

The goal of radiotherapy (RT) in the treatment of cancer is to deliver as much radiation dose to the tumour, whilst minimising the amount of dose delivered to the surrounding normal tissue. Proton beam therapy (PBT) is an alternate form of RT, delivering high energy particles (protons) rather than conventional x-rays (photons) to a tumour. The favourable dose deposition of protons follows a low entrance dose culminating in a steep dose gradient and rapid fall off (Bragg peak), increasing the precision of the dose delivery to the tumour. Due to the overall cost and technology required to generate protons, experiments are often performed in dedicated research rooms within a clinical department, using equipment designed for human treatment. The significant size difference between a human and a mouse makes it difficult to utilise the Bragg peak dose distribution within the small animal so often the initial plateau region of the beam is used to irradiate the target. However, this means the beam extends beyond the target as the beam energy is too high to be attenuated by the small animal and, consequently, healthy tissue is irradiated increasing toxicity. To improve the precision of the irradiation, and scale down the beam to the small animal size, a variety of techniques and equipment across institutions are used, including range shifters, energy degraders, shielding or collimators.The aim of this study is to adapt a previously developed 3D printed mouse-shaped tool (phantom) to measure proton dose using radiochromic film to ensure accurate proton dose delivery at the small animal scale in our laboratory. We aim to validate this against measurements of DNA damage in 3D matrices of tumour cells encapsulated in a hydrogel bead. Following this, the phantom will be delivered to multiple international institutions as part of a dose measurement audit, testing the techniques used and comparing the planned and delivered doses. This will be facilitated through our existing collaborations with the Inspire project and the Particle Therapy Co-operative Group (PTCOG). Currently, a small number of animals (~200) are used in pilot studies to test the suitability of different equipment to reduce the beam size to suit specific experiments. Through the multicentre audit we aim to show direct users that the phantom we have developed can be a suitable replacement for these animals. The phantom can also be used as a mouse substitute to refine experiments and streamline the set-up, reducing the time the animals are under anaesthesia or immobilised. According to a literature search, in the last 5 years ~1300 mice were used in proton research but this number is set to rise as proton beam technology becomes more widely available. Regular use of the tool to measure the dose output and identify any problems will increase confidence in the results, therefore reducing the numbers of animal required to achieve statistically significant data and refining the dose delivery to minimise potential toxicity.