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.
Highlights
Radiotherapy treatment of tumors is used in approximately 50% of all cancer cases worldwide and is besides chemotherapy, surgery and immunotherapy one of the four pillars of cancer treatment throughout the last decades [1,2,3,4]
Preclinical studies conducted at the ion microprobe SNAKE (Superconducting Nanoprobe for Applied nuclear (Kern-) physics Experiments) [37, 38] in a mouse ear model showed that acute side effects in normal tissue are reduced by using proton minibeam radiotherapy (pMBRT) with PVDR 540 compared to quasi homogeneous irradiation (PVDR 1–1.2) when pencil spot beams are applied with sizes in the range of 0.1–1 mm, a ctc distance of 1.8 mm, and a mean dose of 60 Gy [31, 39]
It will be discussed whether radiofrequency linear accelerators (RF-LINACs), which are currently being developed for standard proton therapy, can be a promising approach to fulfill the technical requirements
Summary
Radiotherapy treatment of tumors is used in approximately 50% of all cancer cases worldwide and is besides chemotherapy, surgery and immunotherapy one of the four pillars of cancer treatment throughout the last decades [1,2,3,4]. Preclinical studies conducted at the ion microprobe SNAKE (Superconducting Nanoprobe for Applied nuclear (Kern-) physics Experiments) [37, 38] in a mouse ear model showed that acute side effects in normal tissue are reduced by using pMBRT with PVDR 540 compared to quasi homogeneous irradiation (PVDR 1–1.2) when pencil spot beams are applied with sizes in the range of 0.1–1 mm, a ctc distance of 1.8 mm, and a mean dose of 60 Gy [31, 39]. The gained knowledge and the experience from the field of X-ray MRT and proton minibeam research will be reassessed for its applicability to the powerful and versatile preclinical testing facility It will be discussed whether radiofrequency linear accelerators (RF-LINACs), which are currently being developed for standard proton therapy, can be a promising approach to fulfill the technical requirements. This will be accompanied by our thoughts on which questions have to be answered and which kinds of tumors are best suited to be treated by pMBRT and should, be included in preclinical studies
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