Proton minibeams: Overcoming proton beams inability to spare superficial tissues

 描述（由申请人提供）：质子治疗在很大程度上被认为是治疗小儿脑肿瘤的首选放射治疗。这主要是因为其 靶的剂量限制由于其布拉格峰特征而优于高能X射线，尽管质子在靶处的略高的相对生物有效性（RBE）也是有帮助的。然而，这些优势仍然没有使质子治疗成为儿科脑肿瘤治疗的理想方法，因为接受质子脑肿瘤治疗的儿童仍然表现出一定程度的晚期认知缺陷。一种解释可能是质子缺乏MV X射线所具有的浅层组织保护效应。这里提出的方法，即质子治疗与minibeams，把固体入射束的质子成阵列的平行，薄（0.3毫米）平面的质子称为minibeams，备用浅组织。当这些微束穿透组织时，由于多重库仑散射，它们逐渐变宽，并且取决于它们之间的间距，它们在一定深度处彼此合并。该深度可以被调整为接近目标的位置。由于儿童的认知损伤在很大程度上来自对他们大脑皮层的辐射损伤，并且由于质子微束应该在很大程度上保留大脑皮层，因此预计质子微束治疗将减少儿童的认知缺陷。该方法与布拉格峰扩展完全兼容。阵列中0.3 mm厚的质子微束之间的最佳束间距在0.7和1.0 mm之间。选择0.7 mm间距值是因为从使用同步加速器微束的研究中已知，微束的组织保护效应将开始下降超过0.7 mm微束厚度，因此中心上0.7-mm的射束间距将产生最大的质子准直器产率而不损害阵列的浅组织保护。我们建议在脑肿瘤和/或正常脑的动物模型中测试这种技术，这是基于这样的假设，即在治疗深部脑肿瘤的同时保留皮层可能会降低治疗的神经认知毒性。目的1比较质子微束和固体束对辐射敏感转基因小鼠APOE 4全脑的辐射效应。目的二：比较质子微束、靶区近端融合和质子固体束治疗大鼠颅内恶性肿瘤9 L胶质肉瘤的效果。将正常大鼠的头部定位在荷瘤大鼠头部的近侧。总的来说，这些实验应该评估该方法的临床应用潜力。成功完成拟议的研究可以给质子治疗一个新的层面，并可能有广泛的质子治疗的临床应用范围从儿科脑肿瘤的治疗，以hypofractionated方案的各种肿瘤，其浅额组织可以固定。

 DESCRIPTION (provided by applicant): Proton therapy is considered, to a large extent, to be the radiation therapy of the choice for treating pediatric brain tumors. This is mostly because its dose confinement to the target is better than that of the high energy x rays due to its Bragg peak feature, although the slightly higher relative biological effectiveness (RBE) of protons at the target is also helpful. However, these advantages still do not make proton therapy an ideal method of pediatric brain tumor therapy because of the fact that children undergoing brain tumor therapy with protons still exhibit a certain level of late cognitive deficits. One explanation coul be that protons lack the shallow-tissue-sparing effect that the MV x rays have. The method proposed here, namely proton therapy with minibeams, turns the solid incident beams of protons into arrays of parallel, thin (0.3 mm) planes of protons called minibeams that spare shallow tissues. As these minibeams penetrate the tissues they gradually broaden because of multiple Coulomb Scattering, and depending on the spacing between them they merge with each other at a certain depth. This depth can be adjusted to be proximal to the target's location. Because the children's cognitive damage comes to a large extent from radiation damage to their cortex, and because proton minibeams should spare the cortex to a large extent, it is expected that proton minibeam therapy will reduce cognitive deficits in children. The method is completely compatible with Bragg-peak spreading. The optimal beam spacing between the 0.3-mm-thick proton minibeams in the arrays is between 0.7 and 1.0 mm. The 0.7 mm spacing value is chosen because it is known from studies with synchrotron minibeams that the minibeam's tissue sparing effect will start to decline beyond 0.7 mm minibeam thickness, and therefore 0.7-mm beam spacing on-center will produce the largest proton collimator yield without compromising the array's shallow-tissue sparing. We propose to test this technique in animal models of brain tumors and/or normal brain based on the hypothesis that sparing the cortex while treating deep-seated brain tumors might reduce the neurocognitive toxicities of treatment. In Aim 1 we compare the radiation effects between proton minibeams and solid beams on the entire brains of the radiosensitive transgenic mice APOE4. In Aim 2 we will treat the intracranial malignant rat brain tumor 9L gliosarcoma comparatively with proton minibeams, merging on the proximal side of the target, and proton solid beams. The head of a normal rat will be positioned proximal to that of the tumor-bearing rats. Collectively these experiments should evaluate the method's potential for clinical use. Successful completion of the proposed research could give a new dimension to proton therapy and could have broad clinical applications for proton therapy ranging from the treatment of pediatric brain tumors to hypofractionated regimens for a variety of tumors whose shallow frontal tissues can be immobilized.