Effect of X-ray minibeam radiation therapy on clonogenic survival of glioma cells

Guardiola, Consuelo; Prezado, Yolanda; Roulin, Christophe; Bergs, Judith

doi:10.1016/j.ctro.2018.07.005

Cited by 12 publications

(11 citation statements)

References 40 publications

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“…This study compared micro‐ and nanodosimetric characteristics of three innovative types of spatially fractionated RT: photon, electron and proton minibeam radiation therapy. xMBRT and pMBRT approaches have been the subject of several dosimetric and biological studies, and these have demonstrated very promising results as a treatment for radioresistant tumors. However, the underlying mechanisms remain unclear.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Calculating the mean cell survival within a unit cell on a percentage scale is therefore independent of the accuracy of the model within the high dose regions. Increased clonogenic cell survival results mainly from the low doses (< 10 Gy) in the valleys where the cell survival is high on a percentage scale and accurately described by the LQ-model as also proposed by Guardiola et al 44 . It needs to be mentioned, that the calculated clonogenic cell survival based on the LQ-model is used as a simple biologically weighted measure for spatially fractionated dose distributions, but precise biological consequences cannot be withdrawn from the data (more details are found in the discussion).…”

Section: Methodsmentioning

confidence: 76%

Optimizing proton minibeam radiotherapy by interlacing and heterogeneous tumor dose on the basis of calculated clonogenic cell survival

Sammer

Girst

Dollinger

2021

Sci Rep

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Proton minibeam radiotherapy (pMBRT) is a spatial fractionation method using sub-millimeter beams at center-to-center (ctc) distances of a few millimeters to widen the therapeutic index by reduction of side effects in normal tissues. Interlaced minibeams from two opposing or four orthogonal directions are calculated to minimize side effects. In particular, heterogeneous dose distributions applied to the tumor are investigated to evaluate optimized sparing capabilities of normal tissues at the close tumor surrounding. A 5 cm thick tumor is considered at 10 cm depth within a 25 cm thick water phantom. Pencil and planar minibeams are interlaced from two (opposing) directions as well as planar beams from four directions. An initial beam size of σ0 = 0.2 mm (standard deviation) is assumed in all cases. Tissue sparing potential is evaluated by calculating mean clonogenic cell survival using a linear-quadratic model on the calculated dose distributions. Interlacing proton minibeams for homogeneous irradiation of the tumor has only minor benefits for the mean clonogenic cell survival compared to unidirectional minibeam irradiation modes. Enhanced mean cell survival, however, is obtained when a heterogeneous dose distribution within the tumor is permitted. The benefits hold true even for an elevated mean tumor dose, which is necessary to avoid cold spots within the tumor in concerns of a prescribed dose. The heterogeneous irradiation of the tumor allows for larger ctc distances. Thus, a high mean cell survival of up to 47% is maintained even close to the tumor edges for single fraction doses in the tumor of at least 10 Gy. Similar benefits would result for heavy ion minibeams with the advantage of smaller minibeams in deep tissue potentially offering even increased tissue sparing. The enhanced mean clonogenic cell survival through large ctc distances for interlaced pMBRT with heterogeneous tumor dose distribution results in optimum tissue sparing potential. The calculations show the largest enhancement of the mean cell survival in normal tissue for high-dose fractions. Thus, hypo-fractionation or even single dose fractions become possible for tumor irradiation. A widened therapeutic index at big cost reductions is offered by interlaced proton or heavy ion minibeam therapy.

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“…We demonstrated a more accessible method for applying MRT [ 15 ]. Recently, several groups have begun to employ comparable methods for physical, biological and preclinical studies, proving the high reproducibility of this approach [ 29 , 30 , 31 , 32 , 33 , 34 ]. Here, the evaluations of the treatment efficacy of MRT on the murine melanoma model confirmed our previous results.…”

Section: Discussionmentioning

confidence: 99%

Immune-Mediated Effects of Microplanar Radiotherapy with a Small Animal Irradiator

Bazyar

Benefield

Roberts

et al. 2021

Cancers

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Spatially fractionated radiotherapy has been shown to have effects on the immune system that differ from conventional radiotherapy (CRT). We compared several aspects of the immune response to CRT relative to a model of spatially fractionated radiotherapy (RT), termed microplanar radiotherapy (MRT). MRT delivers hundreds of grays of radiation in submillimeter beams (peak), separated by non-radiated volumes (valley). We have developed a preclinical method to apply MRT by a commercial small animal irradiator. Using a B16-F10 murine melanoma model, we first evaluated the in vitro and in vivo effect of MRT, which demonstrated significant treatment superiority relative to CRT. Interestingly, we observed insignificant treatment responses when MRT was applied to Rag−/− and CD8-depleted mice. An immuno-histological analysis showed that MRT recruited cytotoxic lymphocytes (CD8), while suppressing the number of regulatory T cells (Tregs). Using RT-qPCR, we observed that, compared to CRT, MRT, up to the dose that we applied, significantly increased and did not saturate CXCL9 expression, a cytokine that plays a crucial role in the attraction of activated T cells. Finally, MRT combined with anti-CTLA-4 ablated the tumor in half of the cases, and induced prolonged systemic antitumor immunity.

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Effect of X-ray minibeam radiation therapy on clonogenic survival of glioma cells

Abstract: HighlightsFirst in vitro study performed in an X-ray SARRP for minibeam irradiations.At equal mean dose, the same tumor control can be obtained with standard and minibeam irradiations.This contradicts the established paradigms of the standard radiation therapy.

Cited by 12 publications

References 40 publications

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

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

Optimizing proton minibeam radiotherapy by interlacing and heterogeneous tumor dose on the basis of calculated clonogenic cell survival

Immune-Mediated Effects of Microplanar Radiotherapy with a Small Animal Irradiator

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