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Background: 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. Such preclinical results encourage the preparation of clinical trials. Purpose: In this study, the potential of pMBRT for treating clinical indications candidates for the first clinical trials (i.e., brain, lung, and liver metastases) was evaluated. Methods: Four clinical cases, initially treated with stereotactic radiotherapy (SRT),were selected for this study.pMBRT,SRT,and conventional proton therapy (PT) dose distributions were compared by using three main criteria: (i) the tumor coverage, (ii) the mean dose to organs-at-risk, and (iii) the possible adverse effects in normal tissues by considering valley doses as the responsible for tissue sparing. pMBRT plans consisted of one fraction and one–two fields. Dose calculations were computed by means of Monte Carlo simulations. Results: pMBRT treatments provide a similar or superior target coverage than SRT, even using fewer fields. pMBRT also significantly reduces the biologically effective dose (BED) to organs-at-risk. In addition, valley and mean doses to normal tissues remain below tolerance limits when treatments are delivered in a single fraction, contrary to PT treatments. Conclusions: This work provides a first insight into the possibility of treating metastases with pMBRT. More favorable dose distributions and treatment delivery regimes may be expected from this new approach than SRT.The advantages of pMBRT would need to be confirmed by means of Phase I clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Normal tissue's morbidity continues to limit the increase in the therapeutic index in radiation therapy. This study explores the potential advantages of combining proton arc therapy and proton minibeam radiation therapy, which have already individually shown a significant normal tissue's sparing. This alliance aims to integrate the benefits of those techniques in a single approach. (1) Background: Proton Arc Therapy and Proton Minibeam Radiation Therapy are two novel therapeutic approaches with the potential to lower the normal tissue complication probability, widening the therapeutic window for radioresistant tumors. While the benefits of both modalities have been individually evaluated, their combination and its potential advantages are being assessed in this proof-of-concept study for the first time. (2) Methods: Monte Carlo simulations were employed to evaluate the dose and LET distributions in brain tumor irradiations. (3) Results: a net reduction in the dose to normal tissues (up to 90%), and the preservation of the spatial fractionation of the dose were achieved for all configurations evaluated. Additionally, Proton Minibeam Arc Therapy (pMBAT) reduces the volumes exposed to high-dose and high-LET values at expense of increased low-dose and intermediate-LET values. (4) Conclusions: pMBAT enhances the individual benefits of proton minibeams while keeping those of conventional proton arc therapy. These results might facilitate the path towards patients' treatments since lower peak doses in normal tissues would be needed than in the case of a single array of proton minibeams. [ABSTRACT FROM AUTHOR]

Simple Summary: Healthy tissue tolerance to radiation is one of the main limitations in radiotherapy treatment. To broaden the therapeutic index, innovative approaches using non-conventional spatial and temporal beam structure are currently being investigated. Among them, proton minibeam radiation therapy is a promising solution that has already shown a remarkable increase in healthy tissue tolerance in various preclinical models. The purpose of this study is to propose potential strategies to further optimize proton minibeam spatial modulation with the use of magnetic fields. By generating a converging minibeam pattern with dipole magnetic fields, we show that spatial modulation can be improved at shallow depth for the same dose distribution at the tumor location. This indicates that proton minibeam radiation therapy could be efficiently combined with magnetic fields to further increase healthy tissue tolerance. Proton MiniBeam Radiation Therapy (pMBRT) is a novel strategy that combines the benefits of minibeam radiation therapy with the more precise ballistics of protons to further optimize the dose distribution and reduce radiation side effects. The aim of this study is to investigate possible strategies to couple pMBRT with dipole magnetic fields to generate a converging minibeam pattern and increase the center-to-center distance between minibeams. Magnetic field optimization was performed so as to obtain the same transverse dose profile at the Bragg peak position as in a reference configuration with no magnetic field. Monte Carlo simulations reproducing realistic pencil beam scanning settings were used to compute the dose in a water phantom. We analyzed different minibeam generation techniques, such as the use of a static multislit collimator or a dynamic aperture, and different magnetic field positions, i.e., before or within the water phantom. The best results were obtained using a dynamic aperture coupled with a magnetic field within the water phantom. For a center-to-center distance increase from 4 mm to 6 mm, we obtained an increase of peak-to-valley dose ratio and decrease of valley dose above 50%. The results indicate that magnetic fields can be effectively used to improve the spatial modulation at shallow depth for enhanced healthy tissue sparing. [ABSTRACT FROM AUTHOR]

Simple Summary: Proton minibeam radiation therapy (pMBRT) is a novel therapeutic approach based on a distinct dose delivery method: the dose distributions follow a pattern with regions of peaks (high doses) and valleys (low doses). pMBRT was shown to be able to widen the therapeutic window in glioma-bearing rats. In previous studies the irradiation was performed in one single fraction. The work reported in this manuscript is the first evaluation detailing the response of glioma-bearing rats to a temporal fractionation in proton minibeam radiation therapy, delivered under a crossfire geometry. A significant increase of the median survival time was obtained when the dose was delivered over two sessions as opposed to in a single fraction. This result could facilitate the path towards pMBRT treatments. (1) Background: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy technique using spatially modulated narrow proton beams. pMBRT results in a significantly reduced local tissue toxicity while maintaining or even increasing the tumor control efficacy as compared to conventional radiotherapy in small animal experiments. In all the experiments performed up to date in tumor bearing animals, the dose was delivered in one single fraction. This is the first assessment on the impact of a temporal fractionation scheme on the response of glioma-bearing animals to pMBRT. (2) Methods: glioma-bearing rats were irradiated with pMBRT using a crossfire geometry. The response of the irradiated animals in one and two fractions was compared. An additional group of animals was also treated with conventional broad beam irradiations. (3) Results: pMBRT delivered in two fractions at the biological equivalent dose corresponding to one fraction resulted in the highest median survival time, with 80% long-term survivors free of tumors. No increase in local toxicity was noted in this group with respect to the other pMBRT irradiated groups. Conventional broad beam irradiations resulted in the most severe local toxicity. (4) Conclusion: Temporal fractionation increases the therapeutic index in pMBRT and could ease the path towards clinical trials. [ABSTRACT FROM AUTHOR]