Development and characterization of the first proton minibeam system for single-gantry proton facility.

Minibeam represents a preclinical spatially fractionated radiotherapy modality with great translational potential. The advantage lies in its high therapeutic index (compared to GRID and LATTICE) and ability to treat at greater depth (compared to microbeam). Proton minibeam radiotherapy (pMBRT) is a synergy of proton and minibeam. While the single-gantry proton facility has gained popularity due to its affordability and compact design, it often has limited beam time available for research purposes. Conversely, given the current requirement of pMBRT on specific minibeam hardware collimators, necessitates a reproducible and fast setup to minimize pMBRT treatment time and streamline the switching time between pMBRT and conventional treatment for clinically translation. The contribution of this work is the development and characterization of the first pMBRT system tailored for single-gantry proton facility. The system allows for efficient and reproducible plug-and-play setup, achievable within minutes. The single room pMBRT system is constructed based on IBA ProteusONE proton machine. The end of nozzle is attached with beam modifying accessories though an accessory drawer. A small snout is attached to the accessory drawer and used to hold apertures and range shifters. The minibeam aperture consists of two components: a fitting ring and an aperture body. Three minibeam apertures were manufactured. The first-generation apertures underwent qualitatively analysis with film, and the second generation aperture underwent more comprehensive quantitative measurement. The reproducibility of the setup is accessed, and the film measurements are performed to characterize the pMBRT system in cross validation with Monte Carlo (MC) simulations. We presented initial results of large field pMBRT aperture and the film measurements indicates the effect of source-to-isocenter distance = 930 cm in Y proton scanning direction. Consistent with TOPAS MC simulation, the dose uniformity of pMBRT field <2 cm is demonstrated to be better than 2%, rendering its suitability for pre-clinical studies. Subsequently, we developed the second generation of aperture with five slits and characterized the aperture with film dosimetry studies and compared the results to the benchmark MC. Comprehensive film measurements were also performed to evaluate the effect of divergence, air gap and gantry-angle dependency and repeatability and revealing a consistent performance within 5%. Furthermore, the 2D gamma analysis indicated a passing rate exceeding 99% using 3% dose difference and 0.2 mm distance agreement criteria. We also establish the peak valley dose ratio and the depth dose profile measurements, and the results are within 10% from MC simulation. We have developed the first pMBRT system tailored for a single-gantry proton facility, which has demonstrated accuracy in benchmark with MC simulations, and allows for efficient plug-and-play setup, emphasizing efficiency.

Lin Y ，Li W ，Johnson D ，Prezado Y ，Gan GN ，Gao H ... -  《-》

Comprehensive dosimetric commissioning of proton minibeam radiotherapy on a single gantry proton system.

Proton minibeam radiation therapy (pMBRT) can deliver spatially fractionated dose distributions with submillimeter resolution. These dose distributions exhibit significant heterogeneity in both depth and lateral directions. Accurate characterization of pMBRT doses requires dosimetry devices with high spatial resolution and a wide dynamic range. Furthermore, the dependency of dosimetric measurements on Linear Energy Transfer (LET), as observed in conventional proton therapy, is also present in pMBRT depth dose measurements. This work demonstrates the process of performing comprehensive dosimetric measurements to characterize the pMBRT collimator on a clinical single-gantry proton machine, utilizing commercially available dosimetry devices. The minibeam collimator is designed to be mounted on the clinical nozzle as a beam-modifying accessory. Three collimators, each with a slit opening of 0.4 mm, are thoroughly evaluated. The center-to-center (c-t-c) distances of the slits for these collimators are 2.8 mm, 3.2 mm, and 4.0 mm, respectively. High spatial resolution dosimetry devices are essential for PMBRT dose characterizations. To meet this requirement, two-dimensional (2D) dose measurement devices, Gafchromic films, are used to measure lateral profiles at various depths. Films are also used for depth dose profile measurements in solid water. Additionally, high-resolution point dose detectors, microDiamond, and Razor diode detectors are employed for lateral profile measurements at various depths. Percent depth dose (PDD) measurements of pMBRT in solid water, with various proton energies, collimators, and air gaps, are performed using Gafchromic films. The film's LET dependency for proton beams is corrected to ensure accurate pMBRT PDD measurements. The Monte Carlo simulation tool TOPAS is utilized to compare and validate all experimental measurements. At depths where LET is not a concern, film dose measurements were consistent with microDiamond and Razor diode point measurements. The point detectors need to be orientated with the thin side aligned to the incoming beam. Comparison of the lateral dose profiles extracted from TOPAS simulations, films, microDiamond, and Razor diode detectors shows a passing rate exceeding 98% in 1D gamma analysis at 3% 0.1 mm criteria.However, when the microDiamond detector is orientated to face the pMBRT beam, its spatial resolution may not be sufficient to capture the peak and valley dose accurately. Nevertheless, an accuracy within 2% can still be achieved when comparing the average dose. The PDD measurements show that the peak valley dose ratio (PVDR) of pMBRT can be altered at different depths with different air gaps using the same collimator or different collimators of different c-t-c distances. Our study demonstrates that comprehensive dose measurements for pMBRT can be conducted using standard clinical dose measurement devices. These measurements are indispensable for guiding and ensuring accurate dose reporting in pre-clinical studies using the pMBRT technique.

Lin Y ，Li W ，Wang A ，Johnson D ，Gan GN ，Gao H ... -  《Frontiers in Oncology》

Implementation of planar proton minibeam radiation therapy using a pencil beam scanning system: A proof of concept study.

Proton minibeam radiation therapy (pMBRT) is an innovative approach that combines the advantages of minibeam radiation therapy with the more precise ballistics of protons to further reduce the side effects of radiation. One of the main challenges of this approach is the generation of very narrow proton pencil beams with an adequate dose-rate to treat patients within a reasonable treatment time (several minutes) in existing clinical facilities. The aim of this study was to demonstrate the feasibility of implementing pMBRT by combining the pencil beam scanning (PBS) technique with the use of multislit collimators. This proof of concept study of pMBRT with a clinical system is intended to guide upcoming biological experiments. Monte Carlo simulations (TOPAS v3.1.p2) were used to design a suitable multislit collimator to implement planar pMBRT for conventional pencil beam scanning settings. Dose distributions (depth-dose curves, lateral profiles, Peak-to-Valley Dose Ratio (PVDR) and dose-rates) for different proton beam energies were assessed by means of Monte Carlo simulations and experimental measurements in a water tank using commercial ionization chambers and a new p-type silicon diode, the IBA RAZOR. An analytical intensity-modulated dose calculation algorithm designed to optimize the weight of individual Bragg peaks composing the field was also developed and validated. Proton minibeams were then obtained using a brass multislit collimator with five slits measuring 2 cm × 400 μm in width with a center-to-center distance of 4 mm. The measured and calculated dose distributions (depth-dose curves and lateral profiles) showed a good agreement. Spread-out Bragg peaks (SOBP) and homogeneous dose distributions around the target were obtained by means of intensity modulation of Bragg peaks, while maintaining spatial fractionation at shallow depths. Mean dose-rates of 0.12 and 0.09 Gy/s were obtained for one iso-energy layer and a SOBP conditions in the presence of multislit collimator. This study demonstrates the feasibility of implementing pMBRT on a PBS system. It also confirms the reliability of RAZOR detector for pMBRT dosimetry. This newly developed experimental methodology will support the design of future preclinical research with pMBRT.

De Marzi L ，Patriarca A ，Nauraye C ，Hierso E ，Dendale R ，Guardiola C ，Prezado Y ... -  《-》

Preclinical dosimetry in proton minibeam radiation therapy: Robustness analysis and guidelines.

Proton minibeam radiation therapy (pMBRT) is a new radiotherapy approach that has shown a significant increase in the therapeutic window in glioma-bearing rats compared to conventional proton therapy. The dosimetry of pMBRT is challenging and error prone due to the submillimetric beamlet sizes used. The aim of this study was to perform a robustness analysis on the setup parameters utilized in current preclinical trials and provide guidelines for reproducible dosimetry. The results of this work are intended to guide upcoming implementations of pMBRT worldwide, as well as pave the way for future clinical implementations. Monte Carlo simulations and experimental data were used to evaluate the impact of variations in setup parameters and uncertainties in collimator specifications on lateral pMBRT dose distributions. The value of each parameter was modified individually to evaluate their effect on dose distributions. Experimental dosimetry was performed by means of high-resolution detectors, that is, radiochromic films, the IBA Razor and the Microdiamond detector. New guidelines were proposed to optimize the experimental setup in pMBRT studies and perform reproducible dosimetry. The sensitivity of dose distributions to uncertainties and variations in setup parameters was quantified. Quantities that define pMBRT lateral profiles (i.e., the peak-to-valley dose ratio [PVDR], peak and valley doses, and peak width) are significantly influenced by small-scale fluctuations in several of those parameters. The setup implemented at the Orsay proton therapy center for pMBRT irradiation was optimized to increase PVDRs and peak symmetry. In addition, we proposed guidelines to perform accurate and reproducible dosimetry in preclinical studies. This study revealed the importance of adopting guidelines and protocols tailored to the distinct dose delivery method and dose distributions in pMBRT. This new methodology leads to reproducible dosimetry, which is imperative in preclinical trials. The results and guidelines presented in this manuscript can ease the initiation of pMBRT investigations in other centers.

Ortiz R ，De Marzi L ，Prezado Y 《-》

Design and characterization of an aperture system and spot configuration for ocular treatments with a gantry-based spot scanning proton beam.

Proton therapy is a key modality used in the treatment of ocular melanoma. Traditionally ocular sites are treated using a dedicated eyeline with a passively scattered proton beam and a brass aperture. This work aims to design and characterize a beam-collimating aperture to treat ocular targets with a gantry-based spot scanning proton beam. A plastic aperture system that slides into the gantry nozzle of a spot scanning proton beam was designed and constructed. It consists of an intermediate scraper layer to attenuate stray protons and a 3D-printed patient-specific aperture positioned 5.7 cm from the surface of the eye. The aperture system was modeled in TOPAS and Monte Carlo simulations were validated with film measurements. Two different spot configurations were investigated for treatment planning and characterized based on lateral penumbra, central axis (CAX) dose and relative efficiency. Alignment and leakage were investigated through experimental film measurements. Range was verified using a multi-layer ionization chamber. Reference dose measurements were made with a PinPoint 3D ion chamber. Neutron dose was evaluated through Monte Carlo simulations. Aperture alignment with radiation isocenter was determined to be within 0.31 mm at a gantry angle of 0°. A single-spot configuration with a 10 mm diameter aperture yielded film-measured lateral penumbras of 1 mm to 1.25 mm, depending on depth in the spread-out Bragg peak. TOPAS simulations found that a single spot configuration results in a flat dose distribution for a 10 mm diameter aperture and provides a CAX dose of less than 106% for apertures less than 14 mm in diameter. For larger targets, adding four corner spots to fill in the dose distribution is beneficial. Trade-offs between lateral penumbra, CAX dose and relative efficiency were characterized for different spot configurations and can be used for future clinical decision-making. The aperture was experimentally determined to not affect proton beam range, and no concerning leakage radiation or neutron dose was identified. Reference dose measurements with a PinPoint ion chamber were within 2.1% of Monte Carlo calculated doses. The aperture system developed in this work provides a method of treating ocular sites on a gantry-based spot scanning proton system. Additional work to develop compatible gaze tracking and gating infrastructure is ongoing.

Hickling SV ，Corner S ，Kruse JJ ，Deisher AJ ... -  《-》