A 3D range-modulator (RM), optimized for a single energy and a specific target shape, is a promising and viable solution for the ultra-fast dose delivery in particle therapy. The aim of this work was to investigate the impact of potential beam and modulator misalignments on the dose distribution. Moreover, the FLUKA Monte Carlo model, capable of simulating 3D RMs, was adjusted and validated for the 250 MeV single-energy proton irradiation from a Varian ProBeam system. A 3D RM was designed for a cube target shape rotated 45° around two axes using a Varian-internal research version of the Eclipse treatment planning software, and the resulting dose distribution was simulated in a water phantom. Deviations from the ideal alignment were introduced, and the dose distributions from the modified simulations were compared to the original unmodified one. Finally, the FLUKA model and the workflow were validated with base-line data measurements and dose measurements of the manufactured modulator prototype at the HollandPTC facility in Delft. The adjusted FLUKA model, optimized particularly in the scope of a single-energy FLASH irradiation with a PMMA pre-absorber, demonstrated very good agreement with the measured dose distribution resulting from the 3D RM. Dose deviations resulting from modulator-beam axis misalignments depend on the specific 3D RM and its shape, pin aspect ratio, rotation angle, rotation point, etc. A minor modulator shift was found to be more relevant for the distal dose distribution than for the spread-out Bragg Peak (SOBP) homogeneity. On the other hand, a modulator tilt (rotation away from the beam axis) substantially affected not only the depth dose profile, transforming a flat SOBP into a broad, Gaussian-like distribution with increasing rotation angle, but also shifted the lateral dose distribution considerably. This work strives to increase awareness and highlight potential pitfalls as the 3D RM method progresses from a purely research concept to pre-clinical studies and human trials. Ensuring that gantry rotation and the combined weight of RM, PMMA, and aperture do not introduce alignment issues is critical. Given all the other range and positioning uncertainties, etc., not related to the modulator, the RM must be aligned with an accuracy below 1° in order to preserve a clinically acceptable total uncertainty budget. Careful consideration of critical parameters like the pin aspect ratio and possibly a novel robust modulator geometry optimization are potential additional strategies to mitigate the impact of positioning on the resulting dose. Finally, even the rotated cube 3D modulator with high aspect ratio pin structures (~80 mm height to 3 mm pin base width) was found to be relatively robust against a slight misalignment of 0.5° rotation or a 1.5 mm shift in one dimension perpendicular to the beam axis. Given a reliable positioning and QA concept, the additional uncertainties introduced by the 3D RM can be successfully managed adopting the concept into the clinical routine.
三维射程调制器（RM）是一种针对单一能量和特定靶区形状进行优化的装置，为粒子治疗中超快速剂量输送提供了一种前景广阔且可行的解决方案。本研究旨在探讨潜在的束流与调制器对准偏差对剂量分布的影响。此外，对能够模拟三维射程调制器的FLUKA蒙特卡罗模型进行了调整和验证，以适用于瓦里安ProBeam系统产生的250 MeV单能质子照射。利用瓦里安内部研究版的Eclipse治疗计划软件，设计了一个针对绕两个轴旋转45°的立方体靶区形状的三维射程调制器，并在水模体中模拟了由此产生的剂量分布。引入了与理想对准状态的偏差，并将修改后模拟的剂量分布与原始未修改的分布进行了比较。最后，通过在代尔夫特HollandPTC设施进行的基线数据测量和制造的调制器原型剂量测量，对FLUKA模型和工作流程进行了验证。调整后的FLUKA模型，特别是在使用PMMA预吸收体的单能FLASH照射范围内进行了优化，与三维射程调制器产生的测量剂量分布表现出非常好的一致性。调制器-束流轴对准偏差导致的剂量偏差取决于特定的三维射程调制器及其形状、针状结构纵横比、旋转角度、旋转点等。研究发现，微小的调制器平移对远端剂量分布的影响比对展宽布拉格峰（SOBP）均匀性的影响更为显著。另一方面，调制器倾斜（偏离束流轴旋转）不仅会显著影响深度剂量分布，将平坦的SOBP转变为随着旋转角度增加而呈现宽高斯样分布，还会显著改变横向剂量分布。随着三维射程调制器方法从纯粹的研究概念向临床前研究和人体试验发展，本研究致力于提高认识并强调潜在的陷阱。确保机架旋转以及调制器、PMMA和准直器的组合重量不引入对准问题至关重要。考虑到所有其他与调制器无关的射程和定位不确定性等，调制器的对准精度必须低于1°，以保持临床可接受的总不确定性预算。仔细考虑关键参数（如针状结构纵横比）以及可能采用新颖的稳健调制器几何优化，是减轻定位对最终剂量影响的潜在额外策略。最后，研究发现，即使对于具有高纵横比针状结构（约80毫米高度对3毫米针基宽度）的旋转立方体三维调制器，其对0.5°的轻微旋转偏差或垂直于束流轴方向1.5毫米的一维平移也表现出相对稳健性。在具备可靠的定位和质量保证方案的前提下，通过将三维射程调制器概念引入临床常规，可以成功管理其带来的额外不确定性。
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