Proton minibeam radiation therapy spares normal rat brain: Long-Term Clinical, Radiological and Histopathological Analysis

Prezado, Yolanda; Jouvion, Grégory; Hardy, David; Patriarca, Annalisa; Nauraye, C.; Bergs, Judith; González, Wilfredo; Guardiola, Consuelo; Juchaux, Marjorie; Labiod, Dalila; Dendale, R.; Jourdain, Laurène; Sebrié, Catherine; Pouzoulet, F.

doi:10.1038/s41598-017-14786-y

Cited by 85 publications

(121 citation statements)

References 26 publications

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“…Remarkably high normal tissue dose tolerances, and tumor growth delay have been observed in several biological experiments. These outcomes appear to be due to the participation of various biological mechanisms (not yet fully elucidated) that differ from those in standard RT.…”

Section: Introductionmentioning

confidence: 92%

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

et al. 2018

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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.

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Section: Introductionmentioning

confidence: 92%

“…A remarkable increase in normal tissue tolerance has already been demonstrated in pMBRT . In particular, Prezado et al . demonstrated that normal rat brain is able to withstand very high doses (58 Gy peak dose in one fraction) even with minibeams larger than 1 mm (1.1 mm at 1‐cm depth).…”

Section: Introductionmentioning

confidence: 94%

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

et al. 2018

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“…The therapeutic index of radiation therapy (RT) treatments can be notably improved by changing the dose delivery methods, such as the temporal or spatial fractionation of the dose . Minibeam RT (MBRT) is a promising example of how the spatial modulation of the dose can lead to a net reduction in neurotoxicity while providing equivalent or superior tumor control to standard RT for high‐grade gliomas …”

Section: Introductionmentioning

confidence: 99%

“…Recently, the promising potential of a combination of MBRT with charged particle beams has started to be explored . Proton MBRT (pMBRT) was developed on a clinical beam line of the Proton Therapy Center of the Institut Curie (ICPO, Orsay, France) . Previous research demonstrated significant widening of the therapeutic index when pMBRT was applied in preclinical studies .…”

Section: Introductionmentioning

confidence: 99%

Minibeam radiation therapy: A micro‐ and nano‐dosimetry Monte Carlo study

et al. 2020

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Purpose Minibeam radiation therapy (MBRT) is an innovative strategy based on a distinct dose delivery method that is administered using a series of narrow (submillimetric) parallel beams. To shed light on the biological effects of MBRT irradiation, we explored the micro‐ and nanodosimetric characteristics of three promising MBRT modalities (photon, electron, and proton) using Monte Carlo (MC) calculations. Methods Irradiation with proton (100 MeV), electron (300 MeV), and photon (effective energy of 69 keV) minibeams were simulated using Geant4 MC code and the Geant4‐DNA extension, which allows the simulation of energy transfer points with nanometric accuracy. As the target of the simulations, cells containing spherical nuclei with or without a detailed description of the DNA (deoxyribonucleic acid) geometry were placed at different depths in peak and valley regions in a water phantom. The energy deposition and number of events in the cell nuclei were recorded in the microdosimetry study, and the number of DNA breaks and their complexity were determined in the nanodosimetric study, where a multi‐scale simulation approach was used for the latter. For DNA damage assessment, an adapted DBSCAN clustering algorithm was used. To compare the photon MBRT (xMBRT), electron MBRT (eMBRT), and proton MBRT (pMBRT) approaches, we considered the treatment of a brain tumor located at a depth of 75 mm. Results Both mean energy deposition at micrometric scale and DNA damage in the “valley” cell nuclei were very low as compared with these parameters in the peak region at all depths for xMBRT and at depths of 0 to 30 mm and 0 to 50 mm for eMBRT and pMBRT, respectively. Only the charged minibeams were favorable for tumor control by producing similar effects in peak and valley cells after 70 mm. At the micrometer scale, the energy deposited per event pointed to a potential advantage of proton beams for tumor control, as more aggressive events could be expected at the end of their tracks. At the nanometer scale, all three MBRT modalities produced direct clustered DNA breaks, although the majority of damage (>93%) was composed of isolated single strand breaks. The pMBRT led to a significant increase in the proportion of clustered single strand breaks and double‐strand breaks at the end of its range as compared to the entrance (7% at 75 mm vs 3% at 10 mm) in contrast to eMBRT and xMBRT. In the latter cases, the proportions of complex breaks remained constant, irrespective of the depth and region (peak or valley). Conclusions Enhanced normal tissue sparing can be expected with these three MBRT techniques. Among the three modalities, pMBRT offers an additional gain for radioresistant tumors, as it resulted in a higher number of complex DNA damage clusters in the tumor region. These results can aid understanding of the biological mechanisms of MBRT.

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“…This common irradiation method is usually performed to obtain a broad range of LET despite the large uncertainties of LET values mostly near the Bragg peak. In a recent study, Prezado and colleagues demonstrated that a 100‐MeV proton minibeam, corresponding to an estimated LET of about 5 keV/μm at the entrance and 15 keV/μm in the Bragg peak, minimized normal tissue damage in the rat brain compared to broad beam . In addition, several low‐energy proton platforms (of about 3 MeV corresponding to a LET ≈ 12 keV/μm at the entrance of the depth dose curve) allow cell samples' irradiation ranging from the single‐cell scale to in vivo skin irradiation …”

Section: Introductionmentioning

confidence: 99%

Dosimetry and characterization of a 25‐MeV proton beam line for preclinical radiobiology research

et al. 2019

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Purpose With the increase in proton therapy centers, there is a growing need to make progress in preclinical proton radiation biology to give accessible data to medical physicists and practicing radiation oncologists. Methods A cyclotron usually producing radioisotopes with a proton beam at an energy of about 25 MeV after acceleration, was used for radiobiology studies. Depleted silicon surface barrier detectors were used for the beam energy measurement. A complementary metal oxide semiconductor (CMOS) sensor and a plastic scintillator detector were used for fluence measurement, and compared to Geant4 and an in‐house analytical dose modeling developed for this purpose. Also, from the energy measurement of each attenuated beam, the dose‐averaged linear energy transfer (LETd) was calculated with Geant4. Results The measured proton beam energy was 24.85 ± 0.14 MeV with an energy straggling of 127 ± 22 keV before scattering and extraction in air. The measured flatness was within ± 2.1% over 9 mm in diameter. A wide range of LETd is achievable: constant between the entrance and the exit of the cancer cell sample ranging from 2.2 to 8 keV/μm, beyond 20 keV/μm, and an average of 2–5 keV/μm in a scattering spread‐out Bragg peak calculated for an example of a 6‐mm‐thick xenograft tumor. Conclusion The dosimetry and the characterization of a 25‐MeV proton beam line for preclinical radiobiology research was performed by measurements and modeling, demonstrating the feasibility of delivering a proton beam for preclinical in vivo and in vitro studies with LETd of clinical interest.

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Proton minibeam radiation therapy spares normal rat brain: Long-Term Clinical, Radiological and Histopathological Analysis

Cited by 85 publications

References 26 publications

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

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

Minibeam radiation therapy: A micro‐ and nano‐dosimetry Monte Carlo study

Dosimetry and characterization of a 25‐MeV proton beam line for preclinical radiobiology research

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