In the framework of constant research and effort to improve the therapeutic efficacy of deep-seated tumour treatments with external beam radiotherapy (EBRT), different radiation types have been explored in the past. However, the vast majority of treatments are delivered using X-ray radiotherapy, and a smaller fraction of patients is treated with particle therapy (PT) delivered with either protons or heavier ions.

The experience gained so far allowed both IMRT and PT to obtain remarkable results, providing a high level of dose conformity to the target volume. As the therapeutic window of IMRT also depends on normal tissue complication probability, a continuous effort is devoted to improve the sparing of the organs at risk (OARs). In this respect, IMRT and PT treatments have different characteristics and have to be carefully optimised in different ways, providing optimal solutions to different disease sites on the specific position and accessibility of the target volume. As electrons are light-charged particles, their unique features of interaction with matter could be additionally exploited to provide treatments capable of overcoming limitations of IMRT and PT in specific districts or irradiation modalities.

Electrons with energies in the range of 60–120 MeV (VHEE) can be used to treat deep-seated tumours, as they are capable of reaching the needed depth and exhibiting a wide dose peak, whose position changes according to the beam energy. Their use have already been explored in the past [1–3], and a performance comparable with volumetric modulated arc therapy (VMAT) and proton irradiations was demonstrated, at the cost of using a complex irradiation system with many fields (13 or more) or high beam energy (at least 100 MeV) [4, 5]. At the same time, the production of high-energy beams required long accelerating sections that were not easily compatible with existing clinical centres. These conditions contributed, in the past, to make the VHEE solution less cost-effective for a clinical centre with respect to IMRT or other photon-based modalities.

Nowadays, the creation of an accelerating, compact, lower-cost structure for producing high-energy electron fields is possible with the advent of C-band accelerating structures, which is capable of accelerating electrons with the required high charge and fields of up to 50 MeV/m in the hospital setting [6].

In addition, there is increasing evidence from preclinical studies showing that if the dose rate is radically increased (∼40 Gy/s, at least) with respect to conventional treatments (∼0.01 Gy/s), induced radiotoxicity in healthy tissues can be significantly reduced, while maintaining the same cytotoxic effects on cancer cells. Such effects will be further referred to as the FLASH effect [4, 7–9]. The implementation of FLASH beams in clinical centres [10] still has to overcome significant technical challenges. Although FLASH intensities have already been achieved for proton and electron beams (e.g., the low-energy electron beams used for intra-operative radiation therapy), mostly in pre-clinical settings, the implementation of FLASH IMRT with photons is still in its early development stage [8, 11].

The recent advancements in electron accelerating technology, together with the experimental exploration of the FLASH effect, have re-fuelled the interest in the planning and delivery of VHEE for therapeutic applications [12].

In this manuscript, following the approach previously described in [13], the potential of VHEE, with a low number of fields and maximal energy of 130 MeV to treat intracranial lesions, has been studied. The results of conventional irradiation have been compared with state-of-the-art IMRT and PT treatments, and, in addition, the FLASH effect potential for the treatment of such pathologies has been explored.

The first study to explore the feasibility of VHEE to treat deep-seated tumours with a limited number of irradiation fields ([13]) was made on a prostate cancer case, performing comparisons with high-quality results that can be attainable with IMRT and PT at conventional dose rates. In this work, a meningioma and a chordoma case were chosen to investigate how VHEE could be exploited to handle challenging treatments, where the planning target volume (PTV) is closely surrounded by several OARs whose sparing is made difficult by the patient’s anatomy and the corresponding dosimetric prescriptions and constraints. In addition, the reason for choosing this region and, in particular, intracranial lesions to assess the FLASH potential is that they are an excellent ground to test the potential of conventional and FLASH irradiation in providing additional sparing to the OARs that are currently limiting the dose prescription to PTV.

The selected cases, dose prescriptions, dosimetric constraints for the OARs, and the treatment plans optimised at the Trento PT Centre (Azienda Provinciale per i Servizi Sanitari, APSS—Trento ¹ ) are documented. Details are also provided based on the plans optimised in conventional irradiation modality for both IMRT and VHEE. The field’s characteristic definition and the process of VHEE pencil beam fluence optimisation have also been detailed. The comparison of actual delivered plans (protons) and IMRT and VHEE plans with and without including the FLASH effect is presented in the Results section followed by a discussion on the implications of the findings in the landscape of VHEE treatments delivered in both conventional and FLASH modalities.

Two patients who underwent PT in Trento (at the APSS centre) to treat a chordoma (hereinafter, patient C1) and a meningioma (M1) were chosen for this study. The patients were treated with protons using a conventional dose rate (∼Gy/min), and the prescriptions are currently in use at the Trento therapy centre. The target volumes were identified, and the constraints on PTV coverage, OAR sparing, and details on the irradiation approach were defined. More information about the two PT plans, containing the prescriptions expressed in terms of the biological dose and hence in Gy (RBE) or absorbed dose multiplied by the relative biological effectiveness (RBE), is reported as follows:

• Patient M1: Three fields were used, with a prescription to the PTV of 54 Gy(RBE) in 27 fractions. The dosimetric constraints are listed in Table 1.

Both treatment plans had to fulfil the planning goals reported in the corresponding table (1 or 2 for M1 and C1, respectively) for the most relevant OARs identified for each treatment.

The clinical proton plans delivered to the patients were sent to the Medical Physics Unit of Policlinico Umberto I in Rome to carry out the IMRT treatment planning, together with the dose prescriptions, the details about the OARs constraints, and the computed tomography (CT) imaging data. The same information was also used to plan VHEE treatments.

The IMRT plans were optimised assuming a static field delivered on a 6 MV-Elekta Versa HD linear accelerator (Elekta [14]). Plans were optimised using the Pinnacle [15] software suite (RTP system version 16, https://pinnacle-software.com/), according to the prescribed dose and constraints provided by the Trento APSS particle therapy centre. Both plans comprised seven fields and matched the requirements set in Table 1 and Table 2.

The absorbed dose maps for the three techniques (IMRT, PT, and VHEE) were used to compute the DVHs and quantitatively compare the treatment plans. The DVH comparisons are shown in Figure 2 (IMRT vs. VHEE) and Figure 3 (PT vs. VHEE) for M1 and in Figure 4 (IMRT vs. VHEE) and Figure 5 (PT vs. VHEE) for C1.

For plan comparisons, VHEE plan optimisation was performed assuming the same field number and geometry (same gantry angle) as those adopted with the other radiotherapeutic techniques (see also Section 2.1).

The optimised dose maps for all the patients and radiation types are shown in Supplementary Appendix Figures S8, S9 which show the results, respectively, for M1 and C1 using IMRT, PT, and the different VHEE field geometries. The isodose curves are shown in Supplementary Appendix Figures S11, S12.

Figure 2 demonstrates that IMRT and VHEE plans have a comparable quality: while IMRT provides a better PTV coverage, the VHEE irradiation is better at sparing the cochlea. In addition, Figure 3 shows that the VHEE configuration with three fields provides a better PTV coverage than the configurations with seven fields, matching the performance of the PT plan. A quantitative analysis supporting these statements is shown in Table 4, where the values of interest for evaluating the plan goodness are shown for all the M1 treatment plans.

C1 is a more complex case where OAR sparing limits the PTV coverage for all plans. For this reason, priority was given to limit the absorbed dose to the brainstem and spinal cord even if this meant not reaching the desired PTV coverage. For this patient, the DVH analysis of the VHEE configurations with four and seven fields, as shown in Figure 4 and Figure 5, indicates that increasing the number of fields can help in improving the target coverage: the PTV boost coverage shown in the first row in terms of V _95% increases from 85.5% to 90.6%.

The values of V _XX , D _mean , and D ₁ that are used to evaluate the C1 plan are shown in Table 5. Although VHEEs achieve a lower coverage of the PTV, they also result in a better sparing of the spinal cord. The comparison between the irradiation with four and seven fields clearly shows that different geometries can be explored to provide a better sparing of given OARs, and as an example, it is possible to observe that the ear canals, the cochlea, and the parotid glands receive a significantly different mean dose in the two cases.In summary it is possible to conclude that all plans obtained with PT, IMRT, and VHEE, both for M1 and C1, satisfy the constraints and are compatible with the clinical prescriptions.

The potential of VHEE irradiations of intracranial lesions using a small number (between three and seven) of mono-energetic fields and assuming an active-scanning-like beam delivery strategy has been explored.

VHEE with maximum energy of 130 MeV were found to be suitable for the treatment of deep-seated tumours in disease sites with difficult irradiation geometries, allowing a limited number of fields to achieve performances comparable with PT and IMRT. This result, obtained under the assumption of a conventional dose rate, is promising in itself, as it suggests that compact electron accelerators could provide appropriate treatment quality at an affordable cost and with minimal impact on the infrastructures [25], thus providing a valid alternative to PT and IMRT treatments.

The VHEE plans obtained with different irradiation geometries demonstrated that there is a significant room for improvement when trying to optimise not only the beam fluence to cover the target volume but also the field geometry and its energy. The lack of experience in planning treatments with electrons makes it hard to assess if the best possible configurations are the configurations already tested in this manuscript, without an automated tool that can systematically explore the different number of fields, irradiation directions, and beam energies like what is currently performed for photons and protons. The full potential of VHEE will be reassessed once such tool will finally be available.

The beam scanning method used for VHEE treatments allowed us to reach the desired absorbed dose conformity to the PTV while maintaining each field mono-energetic. This condition plays a crucial role when discussing the suitability of VHEE to be used for FLASH therapy irradiations; since there is no need to change the energy within a field, each field can be delivered in a very short time (no more than a few hundred ms), making it easier to achieve an Ultra-High Dose Rate (UHDR) regime. The technological challenge of delivering more than one field in a very short period of time required to ensure FLASH sparing of the OARs is to be addressed yet, but one thing that VHEE plans have in common with proton plans is especially the number of fields that have to be delivered is, in some cases, identical (e.g., the case of M1).

The potential impact of FLASH in terms of OAR sparing has been explored as well, under reasonable assumptions that a maximum sparing effect between 20% and 35% could be achieved, whenever the total absorbed dose in each voxel exceeded the 20 Gy threshold. Meanwhile, although the values of FMF ^m and D _T still need an extensive experimental characterisation and have been assumed to be constant against different types of tissues and independent of the dose rate, the results show that the additional sparing obtained from UHDR would be helpful in improving OAR sparing (e.g., in the case of M1) or allowing for dose escalation that could be used to improve the PTV coverage (as in the case of C1). In both cases, the FLASH effect could be exploited to improve the treatment efficacy, broadening the therapeutic window of the treatment. Both pancreatic cancer and lung cancer seem to be particularly interesting in this respect: hypo-fractionation regimes have already been explored for such treatments, thus representing good candidates to account for the dose and dose rate dependencies of the FMF in a realistic clinical scenario.

The rather basic handling of FLASH effect modelling implemented in this study follows the limited experimental knowledge of the conditions needed to trigger OAR sparing. In this work, no dependence of the FMF on the tissue type or the dose rate was considered. The comparison of the results obtained with FMF equal to 1 (no FLASH effect) and implementing an FMF that has a dose-dependence based on real data with an asymptotic value of 0.8 allow for evaluating the FLASH potential under a robust, well-defined condition that reflects the current best experimental description of the effect. As no fractionation scheme compatible with UHDR irradiations is currently available, for the irradiation of intracranial lesions, we have also decided to maintain the plan constraints coming from the conventional fractionation scheme (2 Gy per fraction). The results presented are not aiming at evaluating which plan, among RT, PT, and VHEE, is the best for the treatment of the specific intracranial lesions used for the simulation study. Instead the main purpose of the presented study is to allow a robust and fair evaluation of the VHEE potential both in conventional and UHDR irradiation modalities.

A refined experimental input, and a better modelling of the FMF, when available, will be used to improve the evaluations presented in this contribution, allowing for a better estimate of the FLASH therapy advantages achievable in a clinical scenario.

The treatment of intracranial lesions with VHEE has been explored. VHEEs were compared against IMRT and PT plans for two patients previously treated with protons, and the results demonstrated that VHEE can achieve performances that are comparable with the state-of-the-art irradiation techniques even in the absence of additional sparing provided by the FLASH effect.

Considering that the VHEE mono-energetic beam interaction with the patient’s tissue results in an absorbed dose distribution that exhibits a very broad peak, and that FLASH rates have already been demonstrated to be deliverable for low-energy electron applications (IOeRT [26, 27]), it was also possible to explore the additional increase that could be achieved when switching to a UHDR configuration. The results demonstrate that under reasonable assumptions on the conditions needed to trigger the FLASH effect, and on its actual value, the FLASH effect could effectively be used to reduce the impact on the OARs surrounding the PTV or to improve the PTV coverage, depending on the actual characteristics of the target volume and the constraints on the OARs crossed by the beam. In all cases and for all particle types, the FLASH effect showed a clear potential in significantly improving the therapeutic window of EBRT treatments.