Preclinical Challenges in Proton Minibeam Radiotherapy: Physics and Biomedical Aspects

Abstract

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.

Conceptual Design of a Novel Nozzle Combined with a Clinical Proton Linac for Magnetically Focussed Minibeams

“…Proton minibeam radiation therapy is a novel therapeutic approach which, in preclinical experiments, has already shown significant increases in the preservation of normal tissue [ 2 , 36 , 37 ] while providing equivalent or superior tumour control [ 3 ]. The optimal implementation of pMBRT should use magnetically focussed and scanned minibeams as this would allow it to maximise the irradiation efficiency and flexibility, decrease the contamination of secondary particles and yield a better spatial fractionation of the dose [ 8 , 9 ].…”

“…An approach to overcome these limitations would be the use of magnetically focussed and scanned minibeams for pMBRT. Indeed, recent publications [ 8 , 9 ] suggest that the optimal implementation of pMBRT should use magnetic focussing instead of mechanical collimation for minibeam generation, as it can significantly increase both the irradiation efficiency and flexibility and also improve the degree of spatial fractionation in healthy tissue.…”

Magnetically focused 70 MeV proton minibeams for preclinical experiments combining a tandem accelerator and a 3 GHz linear post‐accelerator

“…14 Another advantage of beam focusing is that the reduction of the initial beam current resulting from the need to illuminate a collimator surface larger than the holes in it can be avoided. 13 Beam sizes smaller than 0.1 mm and peak-to-valley dose ratios (PVDR) bigger than 10 4 : 1 were already realized for an array of 20 MeV focused proton beams in a skin model study. 5 Small animal studies with deeper located targets are the next step to evaluate the potential of pMBRT for clinical application.…”

“…Pencil minibeam spot scanning may have the best potential of tissue sparing compared to planar minibeams 8,13 . In the past, results from a human skin model 5 and a study within a mouse ear model 9,11,12 and in the rat brain 10 have shown the potential of pMBRT for reduced side effects compared to a homogeneous irradiation.…”

“…Pencil minibeams obtained from beam focusing (rather than by collimation) generate no extra dose by scattered protons from reactions within the collimator 14 . Another advantage of beam focusing is that the reduction of the initial beam current resulting from the need to illuminate a collimator surface larger than the holes in it can be avoided 13 . Beam sizes smaller than 0.1 mm and peak‐to‐valley dose ratios (PVDR) bigger than were already realized for an array of 20 MeV focused proton beams in a skin model study 5 …”