Transformative Technology for FLASH Radiation Therapy

Abstract

The general concept of radiation therapy used in conventional cancer treatment is to increase the therapeutic index by creating a physical dose differential between tumors and normal tissues through precision dose targeting, image guidance, and radiation beams that deliver a radiation dose with high conformality, e.g., protons and ions. However, the treatment and cure are still limited by normal tissue radiation toxicity, with the corresponding side effects. A fundamentally different paradigm for increasing the therapeutic index of radiation therapy has emerged recently, supported by preclinical research, and based on the FLASH radiation effect. FLASH radiation therapy (FLASH-RT) is an ultra-high-dose-rate delivery of a therapeutic radiation dose within a fraction of a second. Experimental studies have shown that normal tissues seem to be universally spared at these high dose rates, whereas tumors are not. While dose delivery conditions to achieve a FLASH effect are not yet fully characterized, it is currently estimated that doses delivered in less than 200 ms produce normal-tissue-sparing effects, yet effectively kill tumor cells. Despite a great opportunity, there are many technical challenges for the accelerator community to create the required dose rates with novel compact accelerators to ensure the safe delivery of FLASH radiation beams.

Keywords: FLASH effect; particle accelerators; radiation therapy.

Figure 1.

Summary of preclinical studies at different accelerator facilities with different radiation types (right panel). Note the irradiation time for delivering 10 Gy on the vertical axis and the IDR of linac pulses or CW bunches on the horizontal axis. The FLASH effect has been observed for a wide IDR range of repeated linac pulses and different types of quasi-CW bunch delivery with iso-cyclotrons and synchrotron radiation light sources. FLASH effects were also seen with single electron pulses with IDR in the range of 10⁶–10⁷ Gy/s and 10⁹–10¹⁰ Gy/s, respectively. Modified from Montay-Gruel P et al. [15]; for references of the individual data points, see that publication. We added the data point from Karsch et al. [16] and grouped the data according to delivery method.

Figure 2.

Schematic view of pulsed beam delivery inducing the FLASH effect. (Reproduced from Wilson et al. [12] under the terms of the Creative Commons Attribution License (CC BY), http://creativecommons.org/licenses/by/4.0/) (accessed on 9 September 2022).

Figure 3.

Layout of the proposed ACCIL design.

Figure 4.

Design, fabrication, and high-power testing of the negative-harmonic traveling-wave structure (NHS) developed by RadiaBeam in collaboration with Argonne.

Figure 5.

Design, cold model, and measurements of the annular-coupled structure (ACS) developed by Argonne in collaboration with RadiaBeam.

Figure 6.

RACCAM multiple-extraction proton therapy FFGA ring. Reproduced with permission from Ref. [49].

Figure 7.

Outer dimensions for a variable energy 330 MeV/nucleon therapeutic ring (left) and a dual ring system of 430 MeV/nucleon (right) compared with the Heidelberg ion therapy facility. On the right, the FLASH-capable, CW, and variable-energy 430-MeV/nucleon ion accelerator nested system is compared to equivalent-energy, low-duty-cycle Heidelberg ion therapy synchrotron. Inner ring racetrack is 250 MeV/nucleon and can provide independent beam delivery.

Figure 8.

Layout of the ramped, bipolar magnet extraction system that selects the orbit and energy for extraction through a septum. Inner, lower-energy orbits are returned to their respective closed orbits for continued acceleration. Reproduced from Ref. [50].

Figure 9.

HIMAC, Japan ion source, and RFQ (left), which serve as the concept for the upstream pre-acceleration system for the injector accelerator (right). A CAD model of the full conceptual design of the 20 MeV/u injector system (scalable to 70–100 MeV/nucleon) is shown on the right. From left to right, the ECR ion source, focusing solenoid, RFQ, beam focusing quadrupoles, and the cyclotron shown with a transparent outer shielding for clarity.

Figure 10.

Figure adapted from Ref. [88]. (a) Schematic depiction of the laser-driven proton beamline at the BELLA PW laser with tape-drive target, active plasma lens, dipole magnet, integrating current transformer (ICT), cell sample, radiochromic film, and scintillator. (b) Cell survival fraction of human prostate cancer cells (PC3) and normal human prostate cells (RWPE1) after irradiation with laser-driven protons. (J. Bin, et al. Sci Rep. 2022 Jan 27;12(1):1484. doi: 10.1038/s41598-022-05181-3, reproduced with permission under the terms of the Creative Commons Attribution License (CC BY), http://creativecommons.org/licenses/by/4.0/) (accessed on 9 September 2022).

Figure 11.

Concept FLASH-RT system using a linear induction accelerator (LIA) providing four or more lines of sight. LIA is on axis with the patient. Blue components are the magnetic focusing elements that direct the electron beam to the patient. The active accelerator is 3.2 m. With the returning drift section, the overall system length is 3.5 m less the patient couch [121]. (Sampayan, S.E.; et al., Sci. Rep. 2021, 11, 17104, https://doi.org/10.3389/fonc.2019.01563 (accessed on 9 September 2022), reproduced with permission under the terms of the Creative Commons Attribution License (CC BY), http://creativecommons.org/licenses/by/4.0/) (accessed on 9 September 2022).

Figure 12.

Measurement geometry, bremsstrahlung field flatness, and pulse-to-pulse repeatability [121]. (Sampayan, S.E.; et al., Sci. Rep. 2021, 11, 17104, https://doi.org/10.3389/fonc.2019.01563 (accessed on 9 September 2022), reproduced with permission under the terms of the Creative Commons Attribution License (CC BY), http://creativecommons.org/licenses/by/4.0/) (accessed on 9 September 2022).

Figure 13.

Rendering of the ROAD FLASH-RT system. A segment of the decoupled MLC ring is shown in the figure inset with three MLC modules. The linac is triggered to produce the beam when the target is aligned with the MLC to produce a VMAT-like treatment.

Figure 14.

FLASH-RT delivery using ROAD. The figure shows four beams with the corresponding pre-shaped MLC in the upper-left corner of respective beams. Cumulative radiation dose to a brain-tumor patient is shown in the center.

Figure 15.

Conceptual diagram of the PHASER architecture with 16 linacs arrayed around the patient for highly conformal FLASH photon therapy. Reproduced with permission from Ref. [141].

Figure 16.

(a) Schematic of cryogenic test setup at XTA using liquid nitrogen. (b) Photo of linac and cryostat assembly prior to installation at XTA. (c) Measurements of accelerating gradient as a function of RF power.

Figure 17.

Schematic of the cryogenic X-band linac for VHEE under development at SLAC.

Figure 18.

SLAC mm-wave linac prototype for high-power testing.

Figure 19.

Electric field profile of the TE11-like mode shown in a cross-section of the deflector cell, with beam axis oriented into the page. The opposing posts (profiles shown in white) produce an RF dipole. Power is coupled in through the port at the top of the model simulated in ANSYS-HFSS.