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Simple Summary: This research aims to improve the precision of particle therapy for lung cancer treatment. The heterogeneous, microscopic structure of lung tissue leads to a broadening of the very sharp dose profiles of protons and other light ions. This can result in higher doses in healthy tissue as well as a reduced dose in the target volume and thereby reducing the potential benefit of particle therapy for lung cancer. This review summarizes existing models that account for these lung tissue effects and explore how they can be better integrated into treatment planning. By taking into account these so called lung modulation effects, it is possible to target tumors more precisely while minimizing harm to surrounding healthy tissues, ultimately benefiting cancer patients. Particle therapy presents a promising alternative to conventional photon therapy for treating non-small cell lung cancer (NSCLC). However, the heterogeneous structure of lung tissue leads to the degradation of the Bragg peak and thereby to the degradation of the dose distribution. This review offers a comprehensive overview of the models developed to account for these modulation effects. It summarizes studies focused on determining modulation power as a predictor of this so-called lung modulation. In addition, the review covers early investigations on dose uncertainties caused by lung modulation in CT-based lung phantoms and patient anatomies and discusses future challenges in integrating these solutions into clinical treatment planning routines. [ABSTRACT FROM AUTHOR]

Simple Summary: Ultra-high dose rate radiotherapy with particle beams such as proton and carbon is a major technical challenge. Fast beam delivery and the concentration of the Bragg peak to the tumor must be achieved in the order of milliseconds and can therefore only be realized with 3D range-modulators (3D RM). This work analyzed the robustness of the dose distribution, resulting from a 3D RM for a cube target volume. Firstly, a high-precision dose measurement was performed, and a very good agreement was found between the measured and Monte Carlo simulated dose distribution. Further simulations were conducted to determine how sensitively the resulting dose distribution responds to misalignments of the 3D RM. The results show that the 3D RM must be aligned with accuracy less than 1° to preserve the planned desired dose distribution. As the research and pre-clinical adoption of 3D RMs in particle therapy has become more widespread recently, these results are of high general utility. 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. [ABSTRACT FROM AUTHOR]

Background: Ultrahigh dose‐rate radiation (UHDR) produces less hydrogen peroxide (H2O2) in pure water, as suggested by some experimental studies, and is used as an argument for the validity of the theory that FLASH spares the normal tissue due to less reactive oxygen species (ROS) production. In contrast, most Monte Carlo simulation studies suggest the opposite. Purpose: We aim to unveil the effect of UHDR on H2O2 production in pure water and its underlying mechanism, to serve as a benchmark for Monte Carlo simulation. We hypothesized that the reaction of solvated electrons (eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $) removing hydroxyl radicals (•OH), the precursor of H2O2, is the reason why UHDR leads to a lower G‐value (molecules/100 eV) for H2O2 (G[H2O2]), because: 1, the third‐order reaction between eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $ and •OH is more sensitive to increased instantaneous ROS concentration by UHDR than a two‐order reaction of •OH self‐reaction producing H2O2; 2, eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $ has two times higher diffusion coefficient and higher reaction rate constant than that of •OH, which means eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $ would dominate the competition for •OH and benefit more from the inter‐track effect of UHDR. Meanwhile, we also experimentally verify the theory of long‐lived radicals causing lower G(H2O2) in conventional irradiation, which is mentioned in some simulation studies. Methods and materials: H2O2 was measured by Amplex UltraRed assay. 430.1 MeV/u carbon ions (50 and 0.1 Gy/s), 9 MeV electrons (600 and 0.62 Gy/s), and 200 kV x‐ray tube (10 and 0.1 Gy/s) were employed. For three kinds of water (real hypoxic: 1% O2; hypoxic: 1% O2 and 5% CO2; and normoxic: 21% O2), unbubbled and bubbled samples with N2O, the scavenger of eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $, were irradiated by carbon ions and electrons with conventional and UHDR at different absolute dose levels. Normoxic water dissolved with sodium nitrate (NaNO3), another scavenger of eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $, and bubbled with N2O was irradiated by x‐ray to verify the results of low‐LET electron beam. Results: UHDR leads to a lower G(H2O2) than conventional irradiation. O2 and CO2 can both increase G(H2O2). N2O increases G(H2O2) of both UHDR and conventional irradiation and eliminates the difference between them for carbon ions. However, N2O decreases G(H2O2) in electron conventional irradiation but increases G(H2O2) in the case of UHDR, ending up with no dose‐rate dependency of G(H2O2). Three‐spilled carbon UHDR does not have a lower G(H2O2) than one‐spilled UHDR. However, the electron beam shows a lower G(H2O2) for three‐spilled UHDR than for one‐spilled UHDR. Normoxic water with N2O or NaNO3 can both eliminate the dose rate dependency of H2O2 production for x‐ray. Conclusions: UHDR has a lower G(H2O2) than the conventional irradiation for both high LET carbon and low LET electron and x‐ray beams. Both scavengers for eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $, N2O and NaNO3, eliminate the dose‐rate dependency of G(H2O2), which suggests eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $ is the reason for decreased G(H2O2) for UHDR. Three‐spilled UHDR versus one‐spilled UHDR indicates that the assumption of residual radicals reducing G(H2O2) of conventional irradiation may only be valid for low LET electron beam. [ABSTRACT FROM AUTHOR]

Background: The integration of magnetic resonance tomography into clinical linear accelerators provides high‐contrast, real‐time imaging during treatment and facilitates online‐adaptive workflows in radiation therapy treatments. The associated magnetic field also bends the trajectories of charged particles via the Lorentz force, which may alter the dose distribution in a patient or a phantom and affects the dose response of dosimetry detectors. Purpose: To perform an experimental and Monte Carlo‐based determination of correction factors kB,Q$k_{B,Q}$, which correct the response of ion chambers in the presence of external magnetic fields in high‐energy photon fields. Methods: The response variation of two different types of ion chambers (Sun Nuclear SNC125c and SNC600c) in strong external magnetic fields was investigated experimentally and by Monte Carlo simulations. The experimental data were acquired at the German National Metrology Institute, PTB, using a clinical linear accelerator with a nominal photon energy of 6 MV and an external electromagnet capable of generating magnetic flux densities of up to 1.5 T in opposite directions. The Monte Carlo simulation geometries corresponded to the experimental setup and additionally to the reference conditions of IAEA TRS‐398. For the latter, the Monte Carlo simulations were performed with two different photon spectra: the 6 MV spectrum of the linear accelerator used for the experimental data acquisition and a 7 MV spectrum of a commercial MRI‐linear accelerator. In each simulation geometry, three different orientations of the external magnetic field, the beam direction and the chamber orientation were investigated. Results: Good agreement was achieved between Monte Carlo simulations and measurements with the SNC125c and SNC600c ionization chambers, with a mean deviation of 0.3% and 0.6%, respectively. The magnitude of the correction factor kB,Q$k_{B,Q}$ strongly depends on the chamber volume and on the orientation of the chamber axis relative to the external magnetic field and the beam directions. It is greater for the SNC600c chamber with a volume of 0.6 cm3 than for the SNC125c chamber with a volume of 0.1 cm3. When the magnetic field direction and the chamber axis coincide, and they are perpendicular to the beam direction, the ion chambers exhibit a calculated overresponse of less than 0.7(6)% (SNC600c) and 0.3(4)% (SNC125c) at 1.5 T and less than 0.3(0)% (SNC600c) and 0.1(3)% (SNC125c) for 0.35 T for nominal beam energies of 6 MV and 7 MV. This chamber orientation should be preferred, as kB,Q$k_{B,Q}$ may increase significantly in other chamber orientations. Due to the special geometry of the guard ring, no dead‐volume effects have been observed in any orientation studied. The results show an intra‐type variation of 0.17% and 0.07% standard uncertainty (k=1) for the SNC125c and SNC600c, respectively. Conclusion: Magnetic field correction factors kB,Q$k_{B,Q}$ for two different ion chambers and for typical clinical photon beam qualities were presented and compared with the few data existing in the literature. The correction factors may be applied in clinical reference dosimetry for existing MRI‐linear accelerators. [ABSTRACT FROM AUTHOR]