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.

Proton therapy has advantages and pitfalls comparing with photon therapy in radiation therapy. Among the limitations of protons in clinical practice we can selectively mention: uncertainties in range, lateral penumbra, deposition of higher LET outside the target, entrance dose, dose in the beam path, dose constraints in critical organs close to the target volume, organ movements and cost. In this review, we combine proposals under study to mitigate those pitfalls by using individually or in combination: (a) biological approaches of beam management in time (very high dose rate “FLASH” irradiations in the order of 100 Gy/s) and (b) modulation in space (a combination of mini-beams of millimetric extent), together with mechanical approaches such as (c) rotational techniques (optimized in partial arcs) and, in an effort to reduce cost, (d) gantry-less delivery systems. In some cases, these proposals are synergic (e.g., FLASH and minibeams), in others they are hardly compatible (mini-beam and rotation). Fixed lines have been used in pioneer centers, or for specific indications (ophthalmic, radiosurgery,…), they logically evolved to isocentric gantries. The present proposals to produce fixed lines are somewhat controversial. Rotational techniques, minibeams and FLASH in proton therapy are making their way, with an increasing degree of complexity in these three approaches, but with a high interest in the basic science and clinical communities. All of them must be proven in clinical applications.

Passive dosimetry with radiochromic films is widely used in proton radiotherapy, both in clinical and scientific environments, thanks to its simplicity, high spatial resolution and dose-rate independence. However, film under-response for low-energy protons, the so-called linear-energy transfer (LET) quenching, must be accounted and corrected for. We perform a meta-analysis on existing film under-response data with EBT, EBT2 and EBT3 GAFchromic™ films and provide a common framework to integrate it, based on the calculation of dose-averaged LET in the active layer of the films. We also report on direct measurements with the 10 MeV proton beam at the Center for Microanalysis of Materials (CMAM) for EBT2, EBT3 and unlaminated EBT3 films, focusing on the 20–80 keV μ m ⁻¹ LET range, where previous data was scarce. Measured film relative efficiency (RE) values are in agreement with previously reported data from the literature. A model on film RE constructed with combined literature and own experimental values in the 5–80 keV μ m ⁻¹ LET range is presented, supporting the hypothesis of a linear decrease of RE with LET, with no remarkable differences between the three types of films analyzed.

Ultra-high dose rate (UHDR) irradiation regimes have the potential to spare normal tissue while keeping equivalent tumoricidal capacity than conventional dose rate radiotherapy (CONV-RT). This has been called the FLASH effect. In this work, we present a new simulation framework aiming to study the production of radical species in water and biological media under different irradiation patterns. The chemical stage (heterogeneous phase) is based on a nonlinear reaction-diffusion model, implemented in GPU. After the first 1 μs, no further radical diffusion is assumed, and radical evolution may be simulated over long periods of hundreds of seconds. Our approach was first validated against previous results in the literature and then employed to assess the influence of different temporal microstructures of dose deposition in the expected biological damage. The variation of the Normal Tissue Complication Probability (NTCP), assuming the model of Labarbe et al., where the integral of the peroxyl radical concentration over time (AUC-ROO) is taken as surrogate for biological damage, is presented for different intra-pulse dose rate and pulse frequency configurations, relevant in the clinical scenario. These simulations yield that overall, mean dose rate and the dose per pulse are the best predictors of biological effects at UHDR.

Background: Recent proposals of high dose rate plans in protontherapy as well as very short proton bunches may pose problems to current beam monitor systems. There is an increasing demand for real‐time proton beam monitoring with high temporal resolution, extended dynamic range and radiation hardness. Plastic scintillators coupled to optical fiber sensors have great potential in this context to become a practical solution towards clinical implementation.Purpose: In this work, we evaluate the capabilities of a very compact fast plastic scintillator with an optical fiber readout by a SiPM and electronics sensor which has been used to provide information on the time structure at the nanosecond level of a clinical proton beam.Materials and methods: A 3 × 3 × 3 mm³ plastic scintillator (EJ‐232Q Eljen Technology) coupled to a 3 × 3 mm² SiPM (MicroFJ‐SMA‐30035, Onsemi) has been characterized with a 70 MeV clinical proton beam accelerated in a Proteus One synchrocyclotron. The signal was read out by a high sampling rate oscilloscope (5 GS/s). By exposing the sensor directly to the proton beam, the time beam profile of individual spots was recorded.Results: Measurements of detector signal have been obtained with a time sampling period of 0.8 ns. Proton bunch period (16 ns), spot (10 μs) and interspot (1 ms) time structures could be observed in the time profile of the detector signal amplitude. From this, the RF frequency of the accelerator has been extracted, which is found to be 64 MHz.Conclusions: The proposed system was able to measure the fine time structure of a clinical proton accelerator online and with ns time resolution.