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

在癌症治疗中，放射治疗（RT）的目标是向肿瘤提供尽可能多的辐射剂量，同时将传递给周围正常组织的剂量降至最低。质子束治疗（PBT）是放射治疗的另一种形式，向肿瘤输送高能粒子（质子）而不是传统的x射线（光子）。质子的有利剂量沉积遵循低入口剂量，最终达到陡峭的剂量梯度和快速下降（布拉格峰），增加了剂量递送到肿瘤的精度。由于产生质子所需的总体成本和技术，实验通常在临床部门的专用研究室进行，使用为人类治疗设计的设备。人类和小鼠之间的显著尺寸差异使得很难在小动物内利用布拉格峰值剂量分布，因此通常使用光束的初始平台区域照射目标。然而，这意味着光束超出了目标，因为光束能量太高，小动物无法减弱，因此，健康组织受到辐射，毒性增加。为了提高辐照精度，并将光束缩小到小动物的尺寸，各机构使用了各种技术和设备，包括范围移位器、能量衰减器、屏蔽或准直器。本研究的目的是采用先前开发的3D打印老鼠形状的工具（幻影）来测量质子剂量，使用放射致色膜来确保在我们实验室的小动物尺度上精确的质子剂量输送。我们的目标是验证这对DNA损伤的测量肿瘤细胞的三维矩阵封装在一个水凝胶珠。在此之后，幻影将作为剂量测量审计的一部分交付给多个国际机构，测试所使用的技术并比较计划和交付的剂量。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，少量动物（约200只）被用于试点研究，以测试不同设备的适用性，以减小光束尺寸以适应特定的实验。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幻影可以成为这些动物的合适替代品。幻影也可以作为老鼠的替代品来完善实验和简化设置，减少动物在麻醉或固定状态下的时间。根据文献检索，在过去的5年里，大约有1300只老鼠被用于质子研究，但随着质子束技术的广泛应用，这个数字将会上升。定期使用该工具来测量剂量输出并确定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，并改进剂量递送以尽量减少潜在毒性。

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.