Purpose Recent in vivo investigations have shown that short pulses of electrons at very high dose rates (FLASH) are less harmful to healthy tissues but just as efficient as conventional dose-rate radiation to inhibit tumor growth. In view of the potential clinical value of FLASH and the availability of modern proton therapy infrastructures to achieve this goal, we herein describe a series of technological developments required to investigate the biology of FLASH irradiation using a commercially available clinical proton therapy system. Methods and Materials Numerical simulations and experimental dosimetric characterization of a modified clinical proton beamline, upstream from the isocenter, were performed with a Monte Carlo toolkit and different detectors. A single scattering system was optimized with a ridge filter and a high current monitoring system. In addition, a submillimetric set-up protocol based on image guidance using a digital camera and an animal positioning system was also developed. Results The dosimetric properties of the resulting beam and monitoring system were characterized; linearity with dose rate and homogeneity for a 12 × 12 mm2 field size were assessed. Dose rates exceeding 40 Gy/s at energies between 138 and 198 MeV were obtained, enabling uniform irradiation for radiobiology investigations of small animals in a modified clinical proton beam line. Conclusions This approach will enable us to conduct FLASH proton therapy experiments on small animals, specifically for mouse lung irradiation. Dose rates exceeding 40 Gy/s were achieved, which was not possible with the conventional clinical mode of the existing beamline.

Experimental Set-up for FLASH Proton Irradiation of Small Animals Using a Clinical System

Ultrahigh dose-rate radiotherapy (RT), or 'FLASH' therapy, has gained significant momentum following various in vivo studies published since 2014 which have demonstrated a reduction in normal tissue toxicity and similar tumor control for FLASH-RT when compared with conventional dose-rate RT. Subsequent studies have sought to investigate the potential for FLASH normal tissue protection and the literature has been since been inundated with publications on FLASH therapies. Today, FLASH-RT is considered by some as having the potential to 'revolutionize radiotherapy'. FLASH-RT is considered by some as having the potential to 'revolutionize radiotherapy'. The goal of this review article is to present the current state of this intriguing RT technique and to review existing publications on FLASH-RT in terms of its physical and biological aspects. In the physics section, the current landscape of ultrahigh dose-rate radiation delivery and dosimetry is presented. Specifically, electron, photon and proton radiation sources capable of delivering ultrahigh dose-rates along with their beam delivery parameters are thoroughly discussed. Additionally, the benefits and drawbacks of radiation detectors suitable for dosimetry in FLASH-RT are presented. The biology section comprises a summary of pioneering in vitro ultrahigh dose-rate studies performed in the 1960s and early 1970s and continues with a summary of the recent literature investigating normal and tumor tissue responses in electron, photon and proton beams. The section is concluded with possible mechanistic explanations of the FLASH normal-tissue protection effect (FLASH effect). Finally, challenges associated with clinical translation of FLASH-RT and its future prospects are critically discussed; specifically, proposed treatment machines and publications on treatment planning for FLASH-RT are reviewed.

https://iopscience.iop.org/article/10.1088/1361-6560/abaa28/pdf

Physics and biology of ultrahigh dose-rate (FLASH) radiotherapy: a topical review

As proton therapy is becoming an established treatment methodology for cancer patients, the number of proton centres is gradually growing worldwide. The economical effort for building these facilities is motivated by the clinical aspects, but might be also supported by the potential relevance for the research community. Experiments with high-energy protons are needed not only for medical physics applications, but represent also an essential part of activities dedicated to detector development, space research, radiation hardness tests, as well as of fundamental research in nuclear and particle physics. Here we present the characterization of the beam line installed in the experimental room of the Trento Proton Therapy Centre (Italy). Measurements of beam spot size and envelope, range verification and proton flux were performed in the energy range between 70 and 228 MeV. Methods for reducing the proton flux from typical treatments values of 106–109 particles/s down to 101–105 particles/s were also investigated. These data confirm that a proton beam produced in a clinical centre build by a commercial company can be exploited for a broad spectrum of experimental activities. The results presented here will be used as a reference for future experiments.

Proton beam characterization in the experimental room of the Trento Proton Therapy facility

Most anticancer radiation therapy facilities are based on linear electron accelerators with electron–photon conversion providing dose-rates in the range 0.03-0.40 Gy.s−1, and treatment plans usually involve daily fractions of 2 Gy cumulated for up to reaching a total dose close to the limit of tolerance of the normal tissues that surround tumors. We recently developed another methodology named “FLASH” that relies on very high dose-rate facilities and consists in delivering ≥ 10 Gy in a single microsecond pulse of relativistic electrons, or else in a limited number of pulses of 1-2 Gy each given in ≤ 100 ms temporal sequence. In mice FLASH was found to elicit a dramatic decrease of damage to normal tissues whilst keeping the anti-tumor efficiency unchanged. In the following we describe the methods used for beam monitoring in the FLASH mode with emphasis on techniques that provide proportional, time-resolved dosimetry of radiation at the submicrosecond time scale. These methods include measurement of the electron fluence, optically monitored chemical dosimeters in water, solid scintillation and Cerenkov light emission. An application to the calibration of Gafchromic™ films is described and the minimal requirements for dose monitoring in preclinical assays are discussed. Good repeatability and linearity of these techniques in a range of peak dose-rates from 2x102 to 4x107 Gy.s−1 and from 1 mGy to over 30 Gy per microsecond pulse have been obtained with an overall precision better than ± 2%.

D. Boi

Papers

Characterization of a commercial scintillation detector for 2-D dosimetry in scanned proton and carbon ion beams.

Dosimetric characterization of a commercial 2-D scintillation detector for quality assurance tests in scanned proton and carbon ion beams