Normal Tissue Response of Combined Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy

Sammer, Matthias; Dombrowsky, Annique C.; Schauer, Jannis; Oleksenko, Kateryna; Bicher, Sandra; Schwarz, Benjamin; Rudigkeit, Sarah; Matejka, Nicole; Reindl, Judith; Bartzsch, Stefan; Blutke, Andreas; Feuchtinger, Annette; Combs, Stephanie E.; Dollinger, G.; Schmid, Thomas E.

doi:10.1016/j.ijrobp.2020.08.027

Cited by 14 publications

(21 citation statements)

References 13 publications

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“…The only previous study evaluating temporally fractionated (4 fractions) pMBRT in normal tissues concluded that at the same level of integral dose, highly dose-modulated fractions spare more than low daily dose-modulated fractions [ 30 ], reflecting the advantages of a high precision repositioning between each fraction.…”

Section: Discussionmentioning

confidence: 99%

First Evaluation of Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy of Glioma-Bearing Rats

Bertho

Ortiz

Juchaux

et al. 2021

Cancers

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(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.

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Section: Discussionmentioning

confidence: 99%

First Evaluation of Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy of Glioma-Bearing Rats

Bertho

Ortiz

Juchaux

et al. 2021

Cancers

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“…In addition, best tissue sparing by overlaid temporal fractionation of minibeam irradiation modes would require a well-adjusted reproduction of the irradiation arrays from one fraction to the next to obtain best overlap of the lateral dose profiles. It has been proven in a mouse ear model that a precise adjustment of four temporal daily fractions results in much better tissue sparing than when each of the temporal fractions was shifted by half a ctc distance 58 . Sub-millimeter positioning of the minibeams from one irradiation to the next requires large technical effort and might be hindered by organ movement.…”

Section: Discussionmentioning

confidence: 99%

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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“…This is independent whether the collimator is illuminated completely by a broad homogeneous dose profile or is scanned by a pencil beam scanning over the entire area of slits. When considering a ratio of irradiated to non-irradiated area of 1 : 100 as already performed in preclinical experiments using a magnetically focused pencil minibeam [31,39,65], the beam current at the target would be reduced at least by a factor of 100 when using a collimator. If the beam current upstream of the collimator cannot be increased, the application would take at least 100 times longer for delivering the same dose to the tumor compared to focused pencil minibeams.…”

Section: Minibeam Irradiation Methods -Collimation Versus Focusingmentioning

confidence: 99%

“…Considering the topic in pMBRT, performing (temporal) fractionated therapy adds another complex parameter in the case of applying submillimeter beams on a day-to-day basis. This issue was already addressed in another preclinical study within the mouse ear model [65]. Here the authors wanted to investigate whether in each (temporal) fraction the very same beam spot locations have to be hit or if the exact spot position on the skin in each fraction is irrelevant.…”

Section: Beam Parameters For a Preclinical Facilitymentioning

confidence: 99%

“…The calculated displacement was corrected using a movable stage with motorized x-and y-axis and also a rotation axis in the plane perpendicular to the beam, where the animal holder was mounted. Using this positioning system, a day-to-day (relative) position accuracy of the ears of 0.1 mm was achieved [65]. For treatment of deeper tumors, the imaging of blood vessels via a camera will not be possible.…”

Section: End Station For Small Animal Irradiationmentioning

confidence: 99%

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Preclinical Challenges in Proton Minibeam Radiotherapy: Physics and Biomedical Aspects

et al. 2020

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The concept of spatial fractionation in radiotherapy was developed for better sparing of normal tissue in the entrance channel of radiation. Spatial fractionation utilizing proton minibeam radiotherapy (pMBRT) promises to be advantageous compared to X-ray minibeams due to higher dose conformity at the tumor. Preclinical in vivo experiments conducted with pMBRT in mouse ear models or in rat brains support the prospects, but the research about the radiobiological mechanisms and the search for adequate application parameters delivering the most beneficial minibeam therapy is still in its infancy. Concerning preclinical research, we consider glioma, non-small cell lung cancer and hepatocellular carcinoma as the most promising targets and propose investigating the effects on healthy tissue, especially neuronal cells and abdominal organs. The experimental setups for preclinical pMBRT used so far follow different technological approaches, and experience technical limitations when addressing the current questions in the field. We review the crucial physics parameters necessary for proton minibeam production and link them to the technological challenges to be solved for providing an optimal research environment. We consider focusing of pencil or planar minibeams in a scanning approach superior compared to collimation due to less beam halos, higher peak-to-valley dose ratios and higher achievable dose rates. A possible solution to serve such a focusing system with a high-quality proton beam at all relevant energies is identified to be a 3 GHz radio-frequency linear accelerator. We propose using a 16 MeV proton beam from an existing tandem accelerator injected into a linear post-accelerator, boosted up to 70 MeV, and finally delivered to an imaging and positioning end-station suitable for small animal irradiation. Ion-optical simulations show that this combination can generate focused proton minibeams with sizes down to 0.1 mm at 18 nA mean proton current - sufficient for all relevant preclinical experiments. This technology is expected to offer powerful and versatile tools for unleashing structured and advanced preclinical pMBRT studies at the limits and also has the potential to enable a next step into precision tumor therapy.

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Normal Tissue Response of Combined Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy

Cited by 14 publications

References 13 publications

First Evaluation of Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy of Glioma-Bearing Rats

First Evaluation of Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy of Glioma-Bearing Rats

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

Preclinical Challenges in Proton Minibeam Radiotherapy: Physics and Biomedical Aspects

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