Uli Weber

Objective. This work provides proof-of-concept for the use of real-time ion imaging and treatment gating for lung cancer radiotherapy using 3D range modulators (3DRM). Approach. The accuracy of a fully real-time, plastic scintillator-based portal ion radiography detector was determined by tracking a 3 cm spherical plastic tumour undergoing breathing-style motion in a mock lung geometry. The ability to gate the delivered treatment using a trigger from the ion radiography detector at the desired tumour position was investigated. Finally, an offline simulated study was performed to compare the dosimetric benefits of the advanced image guidance against the standard clinical motion mitigation practice of rescanning. Main Results. The ion radiography detector was shown to track tumour motion in a mock lung phantom setup to 0.1 mm accuracy. The imaging dose was found to be approximately 1/3 of comparable x-ray fluoroscopy methods. While dynamically driving in the 3DRM is not currently possible, preliminary measurements showed modulator positioning to be reproducible to 0.3%. A technical demonstration was provided showing a real-time switch from imaging to treatment using a trigger from the ion-imaging detector, with the mock tumour found in the expected position. The simulated dosimetric study showed that the tracking accuracy in an idealised scenario allows the tumour to be treated quasi-statically, with a D 95 % of 98% and 99.2% using passive and active treatment beam energy switching respectively. Significance. Lung Ion-fluoroscopy Guided Hadron Therapy (LIGHT) provides a promising approach for (a) mitigating tumour motion using a real-time, in-plane ion imaging device and (b) avoiding interplay effects with scanned beams by using a patient-specific 3D-range modulator to passively scatter a mono-energetic treatment beam. This technique also shows promise for future FLASH treatment delivery methods. Future work will fully determine the tracking performance and dosimetric benefits of LIGHT in more realistic clinical scenarios.

Objective: Accurate estimation of tissue stopping power ratios (SPR) from computed tomography (CT) data is essential in charged particle therapy (CPT), yet it remains a major source of range uncertainties. While various SPR calibration methods have been developed for clinical CT scanners, they are not tailored to cone beam type Micro CT scanners commonly used in pre-clinical studies involving small animals. This work aims to assess how different clinical SPR calibration methods influence range predictions in small animal CPT pre-clinical trials, evaluated at both the voxel and organ levels. Approach: A small animal calibration phantom was imaged with a Micro CT at X-ray tube voltages between 45 kV and 70 kV. The images were used in two single energy (SECT), a stoichiometric and a simplified method, and one stoichiometric dual energy (DECT) calibration method. The accuracy of SPR predictions for each method was evaluated using simulated CT images of murine head, thorax, and abdomen virtual phantoms derived from in vivo data. Main results: Both SECT methods were found to yield comparable accuracy in the head and abdomen areas. Root mean squared (RMS) errors to the nominal SPR values were found to be 5.04% and 4.22% in the head phantom and 2.31% and 2.61% in the abdomen phantom, for the stoichiometric and simplified SECT method, respectively. RMS errors in the lung phantom were found to be 16.42% and 35.80%. The stoichiometric DECT method was found to improve accuracy in the lung phantom to 12.37% while in the head phantom it achieved 19.37% and in the abdomen 6.42%. Significance: This is the first report of treatment plan agnostic low-kV Micro CT SPR calibration accuracy. It can provide a reference for expected SPR and range uncertainties in pre-clinical CPT trials.

Charged particle therapy with protons or heavier ions is one of the most effective radiotherapy techniques, but uncertainties in the beam range can limit its efficacy. Radioactive ion beams are ideal for image-guided particle therapy because isotopes that undergo β⁺ decay can be visualized with positron emission tomography. This allows spatial localization of the particle distribution in vivo, which can be correlated with the expected dose deposition for online beam range verification. Here we report the successful treatment of a mouse osteosarcoma using a radioactive ¹¹C-ion beam. The tumour was located in the neck, close to the spinal cord, where deviations of even a few millimetres in the beam range could lead to unintended dose deposition in the spine and radiation-induced myelopathy, an injury to the spinal cord. We achieved complete tumour control with the highest dose of 20 Gy while avoiding paralysis. Low-grade neurological side effects were correlated to the activity measured by positron emission tomography in the spine. The biological washout of the activity from the tumour volume was dependent on the dose, indicating a potential component of vascular damage at high doses. This experiment marks a step towards future clinical applications of radioactive ion beams.

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.

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.

The COVID-19 pandemic has made clear the need for effective and rapid vaccine development methods. Conventional inactivated virus vaccines, together with new technologies like vector and mRNA vaccines, were the first to be rolled out. However, the traditional methods used for virus inactivation can affect surface-exposed antigen, thereby reducing vaccine efficacy. Gamma rays have been used in the past to inactivate viruses. We recently proposed that high-energy heavy ions may be more suitable as an inactivation method because they increase the damage ratio between the viral nucleic acid and surface proteins. Here, we demonstrate that irradiation of the influenza virus using heavy ion beams constitutes a suitable method to develop effective vaccines, since immunization of mice by the intranasal route with the inactivated virus resulted in the stimulation of strong antigen-specific humoral and cellular immune responses.