The treatment of deep seated tumours with external beam radiotherapy (EBRT) is an effective therapy either in alternative or in addition to surgical removal or chemotherapy. While radiotherapy (RT) with photons is the reference treatment, the number of Particle Therapy (PT) centres delivering protons and carbon ion treatments is steadily increasing in time. Very high energy electrons (energies above a minimum of ~ 50 MeV are needed for an electron to reach a ‘deep’ seated tumour) have been considered in the past. In this paper we evaluate the potential of high energy electron beams according to the recent developments in the field of electrons acceleration and delivery, studying in detail the case of prostate cancer treatment. Prostate cancer has become the third most common cancer in men (nearly 10% of all cancers) and is the fifth leading cause of death worldwide (1, 2).

Early stages of prostate cancer can be treated using Intensity Modulated Radiation Therapy (IMRT) (3–6). One of the IMRT intrinsic limitations is related to how photons interact with the patient body. The absorbed dose peaks 1 or 2 cm (depending on the energy) after entering the patient body while, afterwards, it exponentially decreases along the beam direction.”

The specific interactions of charged particles with matter can help in sparing the OARs, while keeping the same Planning Treatment Volume (PTV) coverage (7, 8) and has been exploited since twenty years in PT which uses protons and carbon ion beams (9, 10). However, an expensive and complex technology with dedicated facilities is needed to exploit proton and carbon beams, resulting in a high initial investment for a PT clinical centre. Furthermore, in PT treatments safety margins have to be introduced to account for uncertainties related to the patient positioning, organs movement, changes in the patient morphology with respect to the imaging used to plan the treatment. The eventual use of electrons, characterised by a broader dose deposition distribution with respect to protons and carbon ions, results in treatment plans that are more robust against range uncertainties, minimising the need of specific safety factors.

Very High Energy Electron (VHEE) beams have thus been explored in literature for the treatment of deep seated tumours. When comparing VHEE treatments with standard RT ones, the conformality of the former absorbed dose distribution to the PTV is comparable with the latter one only at the expense of using a large number of electron fields (order of tens, at least) and a beam energy larger than 100 MeV (11). Both requests contributed, so far, to make the VHEE solution more expensive and technologically challenging for a clinical centre with respect to IMRT or other photon-based RT solutions.

This landscape could change in the near future. Several pre-clinical studies recently claimed that the toxicity in healthy tissues related to tumour treatments can be significantly reduced, while keeping the same efficacy in cancer killing, if the dose rate is radically increased (~50 Gy/s, or even more) with respect to conventional treatments (~0.01 Gy/s). Such effect is known as the FLASH effect (12–14). Recently the first patient affected by a highly resistant skin lymphoma was treated using the FLASH irradiation approach and low energy electron beam (40 MeV) with a promising result (15).

The implementation of FLASH beams in clinical centres still has to overcome significant technical challenges. While the electron beams (in particular the low energy ones, used in Intra-Operative Radiation Therapy) have been already delivered with FLASH intensities, the implementation of FLASH RT with photons is still ongoing (13). Concerning protons, the challenge is related to the development of an ultra-fast energy changing technique capable of fully covering the PTV volume at the dose-rates needed to trigger the FLASH effect (16). To this aim approaches that make use of mono-energetic high energy proton beams have also been proposed.

An example of the different interactions with matter of photons and electrons that can be used to treat deep seated tumours is reported in Figure 1 , showing the energy deposition profile of 10 MeV photons and 100 MeV electrons. The electron dose distribution is characterised by a broad peak that is better suited for the treatment of deep tumours in comparison to photons (see Figure 2 , left). An important feature of the electron dose distribution is its widening as the beam penetrates into the patient, in particular for lower energy, as shown in Figure 2 (right). If the energy of the electron beam is increased well beyond 100 MeV, the beam broadening becomes negligible. As a consequence, using several fields a treatment comparable or better than the standard RT ones can be obtained (7, 8). In the past, such energies were not considered suitable for the clinical practice due to cost, complexity and space encumbrance. However, some of these issues can nowadays be addressed due to recent advances that allow to design compact accelerators matching the required energy with fields up to 50 MeV/m and with very high intensities (17–19).

In this manuscript we focused on the use of VHEE beams, with a low number of fields and taking into account the FLASH effect potential. Recently, a simulation has been carried out to study the feasibility of high energy (40 MeV) electrons FLASH irradiation of paediatric brain tumour with promising results (20). We decided, instead, to use real prostate IMRT treatments to benchmark the FLASH VHEE potential.

To evaluate the potential of VHEE treatments implementing the FLASH effect, we compared the VHEE results with three clinical cases (PZ1, PZ2, PZ3) of prostate tumour treated using IMRT where the irradiation made use of five to seven fields. The tumour (PTV) coverage and the dose absorbed by the OARs have been compared with the results obtained in real IMRT cases, from patients treated at the Department of Radiotherapy, Policlinico Umberto I, “Sapienza” University of Rome, by means of Dose Volume Histograms (DVH).

The clinical target volume consisted of prostates without seminal vesicles. Patients had intermediate-risk prostate cancer and were treated with conventionally fractionated EBRT. PZ1 was treated using 7 fields and had a medical prescription of 78 Gy, PZ2 and PZ3 were treated using 5 fields and had prescriptions of in 78 and 76 Gy respectively. The dose was delivered in 2 Gy fractions, resulting in a total of 39 fractions for PZ1 and PZ2 and 38 fractions for PZ3. A 6 MV-ONCOR Linear Accelerator, produced by Siemens, was used for the treatment.

In the VHEE treatment plan optimisation the calculation of the expected absorbed dose in the patient tissues has been performed using a MC simulation based on the patient Computed Tomography (CT). In the following we present in detail how the MC simulation was performed, how the FLASH effect was implemented and how the plan was optimised using the biological dose distributions.

VHEE treatments have been benchmarked against the results obtained using standard IMRT technique. Figure 4 shows the PZ1, PZ2 and PZ3 IMRT treatment plans optimised using the Pinnacle software (RTP System Version 16, https://pinnacle-software.com/). Three different views of the absorbed dose distribution, overlaid on each patient CT, are shown.

In the VHEE treatment plan the biological dose maps, obtained multiplying the physical dose map by the DMF, have been used to compute each DVH and check the PTV coverage. The results are summarised in Table 3 . The optimised dose maps obtained for an energy of 70 MeV and a DMF of 1 are shown in Figure 5 . The same views and centering points of Figure 4 have been chosen in order to ease the comparison with the results obtained with the conventional IMRT approach.

A more quantitative comparison can be performed studying the DVHs. Figures 6 – 8 show the DVH comparison relative to the dose maps shown respectively in Figures 4 , 5 for PZ1, PZ2 and PZ3.

In addition to the irradiation performed using fields with energies up to 130 MeV, that seems to provide results outperforming the IMRT even with DMF equal to one (no FLASH effect), it is also interesting to note that VHEE of 70 MeV with a DMF different from 1 are also able to provide a treatment that matches the requirements of Table 1 .

Figure 9 shows the DVHs of PZ1 treated using VHEE of 70 MeV. In case of DMF equal to 1 it was not possible to satisfy the PTV coverage requirement. However, if a DMF of 0.8 is taken into account, as shown in Figure 9 left, then the PTV coverage is ensured with an OARs sparing better than the one achievable with IMRT.

The obtained results demonstrate that it is possible, with the same number of fields used in IMRT and energies not exceeding 130 MeV, to optimise a treatment satisfying the PTV coverage constraints while achieving a better sparing of the OARs with respect to photon IMRT, even in absence of FLASH effect.

Summarising, the comparison of the results obtained with VHEE ( Figure 5 and Table 3 ) and with conventional RT ( Figure 4 ), and looking at the DVHs shown in Figures 6 – 8 , suggest that:

These results have been achieved using solid and minimal assumptions: the IMRT irradiation geometry was not changed and it was assumed that the PTV could be covered using the same active scanning methods already implemented in PT treatments (14). We also considered, conservatively, a treatment where all the pencil beams of a given field have the same energy. These assumptions lead unavoidably to a sub-optimal VHEE performance but left open the possibility for further improvements. This consideration is particularly important for the DMF = 1 result, where no FLASH effect has been assumed. Other beam delivery techniques, for example the case in which a wide mono-energetic beam is used to cover the whole are under treatment using a collimator to properly shape the beam so to achieve the required dose conformity to the PTV, will be explored in future papers. That approach simplifies the fulfilment of the dose rate requirement over the whole PTV but poses significant technical challenges, since the FLASH intensity has to be reached on a large volume simultaneously, and implies the use of a passive media that produce additional unwanted secondary radiation whose impact needs to be carefully taken into account.

Concerning the FLASH effect impact, there are few important points that have to be stressed. There is a significant experimental effort currently aiming at determining what is the minimum absorbed dose needed to trigger the effect and what is the maximum time allowed for the irradiation of a given voxel or volume to ensure that an additional sparing is obtained with respect to conventional RT. The results of these studies will definitely affect the beam delivery and the fractionation schemes that will adopted in the future of FLASH RT. In this context, it is clear that the largest benefits will come from those pathologies in which large (≥ 5–6 Gy) doses per fraction are allowed.

In particular, some of the simplifications that we have used when modelling the FLASH effect will have to be abandoned in the future. In this contribution, a constant DMF has been applied to all the healthy tissues and OARs. However, it is unlikely that hypo-fraction scheme will ensure that all the OARs will receive a dose large enough to trigger the FLASH effect. In that sense, for the OARs receiving small doses, the impact of the FLASH effect might be overestimated. At the same time it is also true that the OARs closest to the PTVs, that are mostly affected by the dosimetric constraints, would have the largest benefits from the FLASH effect. A DMF modelling capable of accounting for the dependence on each fraction absorbed dose will be needed to refine the performance evaluation obtained in this work. However we can still conclude that the crude approximation made in our study already hints that impressive results can be obtained even in case of a modest (10–20%) gain in the healthy tissues sparing.

The results presented in this manuscript and obtained on real cases of prostate cancer demonstrate the potential for treating deep seated tumours with external VHEE beams provided by a delivery system implementing the active scanning technique. The implementation of VHEE RT could allow the proper PTV coverage, while achieving a better OARs sparing, with the additional benefit of reducing the impact of range uncertainties (large in PT) in the treatment planning.

Consistently with what already obtained elsewhere (8), without the FLASH effect the energy needed to deliver treatments of comparable efficacy with respect to IMRT or VMAT must be greater than 100 MeV. However, if the FLASH effect is taken into account, lower energies can be exploited opening a new landscape for the clinical implementation of VHEE treatments.

A better evaluation of the potential benefits of FLASH irradiation will be performed once experimental data will be available to determine the absorbed dose threshold needed trigger the effect and the impact of beam delivery strategies. Preliminary results are however promising showing a clear potential for VHEE deep tumor irradiation when delivered at ultra-high dose rates.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ASar, PM, MF, GF, MP, ASch, and VP wrote the main manuscript text. AS, MS, GF, MM, LR, DR, and ASch prepared the figures. ASar, PM, FM, CF, and VT provided the information about the dosimetric constraints that plans have to satisfy and the treatment plan with photons. GB, PM, YD, IM, RM, and SM defined the dose modifying factor modeling inside the optimisation algorithms. LP, ASch, ASci, and ASar provided the information about the beam model to be used in the MonteCarlo simulations. MF, VP, LR, DR, ASar, ASch, GT, MT, and AT implemented the simulation, optimization algorithms, and performed the data analysis. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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