The development of innovative approaches that would reduce the sensitivity of healthy tissues to irradiation while maintaining the efficacy of the treatment on the tumor is of crucial importance for the progress of the efficacy of radiotherapy. Recent methodological developments and innovations, such as scanned beams, ultra-high dose rates, and very high-energy electrons, which may be simultaneously available on new accelerators, would allow for possible radiobiological advantages of very short pulses of ultra-high dose rate (FLASH) therapy for radiation therapy to be considered. In particular, very high-energy electron (VHEE) radiotherapy, in the energy range of 100 to 250 MeV, first proposed in the 2000s, would be particularly interesting both from a ballistic and biological point of view for the establishment of this new type of irradiation technique. In this review, we examine and summarize the current knowledge on VHEE radiotherapy and provide a synthesis of the studies that have been published on various experimental and simulation works. We will also consider the potential for VHEE therapy to be translated into clinical contexts.

After years of lethargy, studies on two non-conventional microstructures in time and space of the beams used in radiation therapy are enjoying a huge revival. The first effect called “FLASH” is based on very high dose-rate irradiation (pulse amplitude ≥106 Gy/s), short beam-on times (≤100 ms) and large single doses (≥10 Gy) as experimental parameters established so far to give biological and potential clinical effects. The second effect relies on the use of arrays of minibeams (e.g., 0.5–1 mm, spaced 1–3.5 mm). Both approaches have been shown to protect healthy tissues as an endpoint that must be clearly specified and could be combined with each other (e.g., minibeams under FLASH conditions). FLASH depends on the presence of oxygen and could proceed from the chemistry of peroxyradicals and a reduced incidence on DNA and membrane damage. Minibeams action could be based on abscopal effects, cell signalling and/or migration of cells between “valleys and hills” present in the non-uniform irradiation field as well as faster repair of vascular damage. Both effects are expected to maintain intact the tumour control probability and might even preserve antitumoural immunological reactions. FLASH in vivo experiments involving Zebrafish, mice, pig and cats have been done with electron beams, while minibeams are an intermediate approach between X-GRID and synchrotron X-ray microbeams radiation. Both have an excellent rationale to converge and be applied with proton beams, combining focusing properties and high dose rates in the beam path of pencil beams, and the inherent advantage of a controlled limited range. A first treatment with electron FLASH (cutaneous lymphoma) has recently been achieved, but clinical trials have neither been presented for FLASH with protons, nor under the minibeam conditions. Better understanding of physical, chemical and biological mechanisms of both effects is essential to optimize the technical developments and devise clinical trials.

(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.

Purpose: The electron linac ElectronFlash installed at Institut Curie (Orsay, France) is entirely dedicated to FLASH irradiation for radiobiological and pre-clinical studies. The system was designed to deliver an ultra-high-dose rate per pulse (UHDR) (above ${10}^6$ Gy/s) and a very high average dose rate at different energies and pulse durations. A campaign of tests and measurements was performed to obtain a full reliable characterizations of the electron beam and of the delivered dose, which are necessary to the radiobiological experiments. Methods: A Faraday cup was used to measure the electron charges in a single RF pulse. The percentage depth dose (PDD) and the transverse dose profiles, at the energies of 5 MeV and 7 MeV, were evaluated employing Gafchromic films EBT-XD for two Poly-methylmethacrylate (PMMA) applicators with irradiation sizes of 30 mm and 120 mm, normally used for in vivo and in vitro experiments, respectively. The results were compared with Monte Carlo (MC) simulations. Results: The measurements were performed during a period of a few months in which the experimental set up was adapted and tuned in order to characterize the electron beam parameters and the values of delivered doses before the radiobiological experiments. The measurements showed that the dose parameters, obtained at the energy of 5 MeV and 7 MeV with different applicators, fulfill the FLASH regime, with a maximum value of an average dose rate of 4750 Gy/s, a maximum dose per pulse of 19 Gy and an instantaneous dose rate up to 4.75 $\times {10}^6$ Gy/s. By means of the PMMA applicators, a very good flatness of the dose profiles was obtained at the cost of a reduced total current. The flatness of the large field is reliable and reproducible in radiobiological experiments. The measured PDD and dose profiles are in good agreement with Monte Carlo simulations with more than $95\%$ of the gamma-index under the thresholds of 3 mm/$3\%$. Conclusions: The results show that the system can provide UHDR pulses totally satisfying the FLASH requirements with very good performances in terms of beam profile flatness for any size of the fields. The monitoring of electron beams and the measurement of the dose parameters played an important role in the in vivo and in vitro irradiation experiments performed at the Institut Curie laboratory.

(1) Background: Proton minibeam radiation therapy (pMBRT) is a novel therapeutic approach with the potential to significantly increase normal tissue sparing while providing tumour control equivalent or superior to standard proton therapy. For reasons of efficiency, flexibility and minibeam quality, the optimal implementation of pMBRT should use magnetically focussed minibeams which, however, could not yet be generated in a clinical environment. In this study, we evaluated our recently proposed minibeam nozzle together with a new clinical proton linac as a potential implementation. (2) Methods: Monte Carlo simulations were performed to determine under which conditions minibeams can be generated and to evaluate the robustness against focussing magnet errors. Moreover, an example of conventional pencil beam scanning irradiation was simulated. (3) Results: Excellent minibeam sizes between 0.6 and 0.9 mm full width at half maximum could be obtained and a good tolerance to errors was observed. Furthermore, the delivery of a 10 cm × 10 cm field with pencil beams was demonstrated. (4) Conclusion: The combination of the new proton linac and minibeam nozzle could represent an optimal implementation of pMBRT by allowing the generation of magnetically focussed minibeams with clinically relevant parameters. It could furthermore be used for conventional pencil beam scanning.