INTRODUCTION

The benefits of FLASH radiotherapy to spare healthy tissues while maintaining effective tumor killing has been demonstrated in a number of different preclinical models (1). Normal tissue sparing by FLASH compared to conventional-dose-rate radiotherapy has been demonstrated for a variety of organ systems (gastrointestinal, brain, skin, lung) (1–6), as well as multiple species (zebrafish, mice, mini-pigs, cats) (1–8), while control of multiple tumor models has remained comparable (lung, breast, head and neck, ovarian, pancreas) (1–8). In 2019 the first human patient was treated for a skin tumor with FLASH using 5.6-MeV electrons, demonstrating favorable tumor control and healthy tissue sparing (7). However, the development of a clinical FLASH system capable for treating typical deep-seated and large volume cancer targets is non-trivial and currently no practical system exists.

Our group is currently developing novel medical linac technology for a pluridirectional high-energy agile scanning electronic radiotherapy (PHASER) system capable of treating cancer with megavoltage (MV) photons at FLASH dose rates (9). A single 10-MV photon beamline is currently being built (to the same specifications as the ultimate multi-beamline PHASER design) for preclinical FLASH radiobiology research, using a linear accelerator structure based on the distributed RF-coupling architecture with genetically optimized cell design (DRAGON) (9, 10) powered by a commercially available 6-MW klystron/modulator RF power source (ScandiNova, Uppsala, Sweden).

In the current work we evaluated the feasibility of repurposing the same accelerator/RF source combination for a “scaled-down” PHASER implementation that could be realized clinically in the near term for selected indications. Although the single 10-MV photon beamline described above will be suitable for preclinical FLASH irradiation of small animals at a relatively short photon source-to-subject distance, different operating parameters would be needed to produce FLASH dose rates for practical clinical scenarios. By treating directly with electrons of sufficiently high energy to produce adequate depth dose, even much lower beam current can produce FLASH dose rates (11–13). Thus, we sought to evaluate an approach of operating this linac at higher accelerating gradient but lower beam current, within the limits of the available RF power source and even though it was not optimized for such parameters.

The configuration evaluated here would deliver treatment with two opposing lateral 40-MeV electron beams (instead of photons) using two accelerators powered by the same common RF power source (Fig. 1A). As a first step in characterizing such a system we used Monte Carlo methods to simulate pediatric whole brain irradiation. This treatment site was chosen as it was suitable for two lateral opposing beams. Additionally, this is a patient population and clinical scenario that would derive the greatest potential benefit of sparing cognitive function postirradiation, which has previously been observed in preclinical experiments with mice when using FLASH in comparison to conventional-dose-rate irradiation (4, 5, 8). We also calculated the beam currents and corresponding dose rates that would be achievable under these operating parameters.

FIG. 1

Panel A: Schematic of beam arrangement for FLASH 40-MeV electron beams. Panel B: Beam's-eye-view of the right-side electron aperture used in the 40-MeV electron plan.

MATERIALS AND METHODS

Beam Current Calculations

The electron beam parameters were based on the DRAGON linear accelerator design currently being built for the preclinical FLASH photon system described above and powered by a commercial 6-MW klystron/modulator RF power source. This linac was designed for ultra-high-dose-rate 10-MV photon irradiation, and as such was optimized for very high electron beam current (beam loading) at 0.3 A peak current and 0.5% duty factor (5 µs pulse length at 1,000 Hz repetition rate, which is within the performance range of the available RF power source) for an average beam current of 1.5 mA at 10 MeV energy.

We calculated the beam current that would be produced when operating the same linac with a higher gradient to produce a 40-MeV electron beam under the same RF power constraint. To produce the higher gradient, the duty factor (pulse length) can be traded for higher peak power through the use of a pulse compressor, of which compact prototypes conservatively capable of four-fold pulse compression have been built (9, 17, 18). Thus, 24 MW of peak input RF power to the accelerator structure, with 1.25 µs pulse length and 1,000 Hz repetition rate (0.125% duty factor), is assumed in this case. Because the design is not optimized for such operation, a substantial portion of the RF input power will be reflected rather than transferred to the beam.

The PHASER linac (designed for 10-MeV energy, 0.3 A peak current) comprises the following structures:

1. A 5-cell injector (RF coupling coefficient: β₁ = 2.59, shunt impedance R_s1 = 3.64 MΩ).

2. A 36-cell linac (RF coupling coefficient: β₂ = 3.86, shunt impedance R_s2 = 85.43 MΩ).

3. A three-port power splitter, which divides the total power of the input port in the ratio of 0.57:3.73 at the two output ports for the five-cell injector and the 36-cell linac, respectively. The relative phases for these two structures are –30° and –150°, respectively.

The reflection from each RF structure is given as:

Here, |Γ_n| is the ratio of the field amplitudes of the reflected RF wave from the structure to that of the incident wave. Also, P_bn is the power gained by the beam and P_wn is the power lost in the walls of the accelerator structure and are given as follows in terms of the beam current I and voltage V_n of the structure,

Using the S-matrix of the three-port splitter with the correct phase along with the above-mentioned relations, we can calculate the various parameters of interest for the 24-MW power at its input port. The results of these calculations are shown in Table 1.

TABLE 1

Calculated Peak Electron Beam Current vs. Beam Energy under Various Operating Parameters Leading to Varying Amounts of Reflected RF Power

RESULTS

Figure 2A shows dose distributions of the 40-MeV electron plan on the top row and the 6-MV photon plan on the bottom row. The range of displayed dose was 0% to 110%, with the mean brain dose of each plan displayed as 100%. The homogeneity index within the brain of the 40-MeV electron plan was 0.133 in comparison to the photon plan's index of 0.087. Based on the ICRU definition of homogeneity, a lower value indicates a more homogeneous dose distribution. Figure 2B shows the DVH for the brain volume of each plan. The plans were normalized for 95% coverage of the brain by the prescription dose (3 Gy). The maximum dose in the 40-MeV plan was 3.6 Gy compared to 3.3 Gy in the photon plan.

FIG. 2

Panel A: Dose distributions of 40-MeV FLASH electron plan generated with Monte Carlo (top row) and 6-MV conventional photon plan calculated in Eclipse (bottom row). Panel B: Dose volume histograms of the 40-MeV FLASH electron plan (red) and the 6-MV photon plan (blue) for the brain volume. The plans were normalized for 95% coverage of the brain by the prescription dose (3 Gy). The 40-MeV electron plan is slightly less homogeneous than the 6-MV photon plan (homogeneity index 0.133 vs. 0.087), although both are clinically acceptable.

Table 1 shows the results of the beam current calculations. Here, P_ref is the power reflected back from the input of the three-port splitter towards the RF source due to mismatched beam loading conditions. In summary, large gains in beam current are possible with a small compromise in beam energy.

From Table 1, conservatively, 5 mA peak current can be produced at a beam energy of 39.5 MeV. Factoring the RF power system's duty factor of 0.125% results in an average electron beam current of 6.25 µA (total of the two opposing beams). Based on the Monte Carlo model, at this beam current the dose rate at isocenter is 115 Gy/s. Of note, there was no appreciable difference between DVHs or homogeneity of plans produced by beams from 39.2- to 40-MeV electron energy (data not shown).

DISCUSSION

As shown in Fig. 2, the 40-MeV electron plan is slightly less homogeneous than the 6-MV photon plan. The “speckled” appearance of the electron plan is due to electron scattering and is magnified by comparison to the photon plan, which is inherently smoothed by the AAA algorithm. The more quantitative measure of homogeneity, the homogeneity index, indicates that both plans are reasonably similar in this aspect, and are in fact both clinically acceptable. The homogeneity of both the electron and photon plan would improve with intensity modulation.

Raster scanning of the electron beam would be a natural way to achieve both the diverging beam geometry for adequate field size and intensity modulation. Modeling the scanning beam was past the scope of this current investigation.

The dose rate of 115 Gy/s is anticipated based on preclinical studies to be more than high enough to achieve the normal tissue sparing benefits of FLASH, which have been demonstrated at dose rates >40 Gy/s (1, 19). In particular, this dose rate is greater than the observed threshold of ∼60 Gy/s for the neurocognitive sparing effect of FLASH (4, 5, 8). As shown in Table 1, by varying the linac parameters, much higher dose rates should be possible with reductions in beam energy small enough to be dosimetrically insignificant. For example, we found no appreciable difference in the plans when the beam energy was reduced from 40 to 39.2 MeV, at which the calculated peak beam current was 20 mA corresponding to a dose rate of 450 Gy/s at the mid-plane of the brain. Thus, even if a simple beam scattering foil is used to produce divergence of the beam, there should be ample current to overcome that inefficiency and maintain FLASH dose rates. Moreover, this performance is achievable despite the linac being optimized for very different operating parameters, and even higher beam current and/or beam energy can be produced for the same RF power if the linac design is optimized accordingly.

We evaluated the feasibility of producing a clinically acceptable pediatric whole brain radiation therapy plan using FLASH 40-MeV electron beams. We anticipate that the same beam configuration would be suitable for other selected clinical scenarios in which parallel opposed beams are often used, e.g., spine or limb radiotherapy. Future directions of this work would include evaluating additional use cases and the performance of linacs specifically optimized for high electron energies in this range.

CONCLUSION

FLASH therapy shows great promise for the treatment of cancer given its ability to spare healthy tissues in comparison to conventional-dose-rate radiotherapy. However, the difficulty of producing treatment beams at the required dose rates to achieve the FLASH effect has been a barrier to the development of a FLASH therapy system capable of treating typical deep-seated and large-volume cancers in humans. This work has preliminarily demonstrated the feasibility of a practically achievable radiotherapy system capable of delivering whole brain irradiation to pediatric patients at FLASH dose rates greater than 100 Gy/s, using an alternative configuration of technology currently being built for preclinical FLASH radiobiology research and therefore realizable in the near future. Such a treatment has the potential to reduce the cognitive decline of pediatric patients after radiation therapy and improve their quality of life. Furthermore, the development of such a system would expand the tools available to the scientific community to more fully assess the potential of FLASH for the treatment of cancer, including that of human patients.