Various in vivo experimental works carried out on different animals and organs have shown that it is possible to reduce the damage caused to healthy tissue still preserving the therapeutic efficacy on the tumor tissue, by drastically reducing the total time of dose delivery (<200 ms). This effect, called the FLASH effect, immediately attracted considerable attention within the radiotherapy community, due to the possibility of widening the therapeutic window and treating effectively tumors which appear radioresistant to conventional techniques. Despite the experimental evidence, the radiobiological mechanisms underlying the FLASH effect and the beam parameters contributing to its optimization are not yet known in details. In order to fully understand the FLASH effect, it might be worthy to investigate some alternatives which can further improve the tools adopted so far, in terms of both linac technology and dosimetric systems. This work investigates the problems and solutions concerning the realization of an electron accelerator dedicated to FLASH therapy and optimized for in vivo experiments. Moreover, the work discusses the saturation problems of the most common radiotherapy dosimeters when used in the very high dose-per-pulse FLASH conditions and provides some preliminary experimental data on their behavior.

Ultra-High dose-per-pulse regimens (UHDP), necessary to trigger the "FLASH" effect, still pose serious challenges to dosimetry. Dosimetry plays a crucial role, both to significantly improve the accuracy of the radiobiological experiments necessary to fully understand the mechanisms underlying the effect and its dependencies on the beam parameters, and to be able to translate such effect into clinical practice. The standard ionization chamber in UHDP region is significantly affected by the effects of the electric field generated by the enormous density of charges produced by the dose pulse. This work describes the theory and the conceptual design of a gas chamber (the ALLS chamber) which overcomes the above-mentioned problems.

The Novac7 and Liac are linear accelerators (linacs) dedicated to intraoperative radiation therapy (IORT), which produce high energy, very high dose-per-pulse electron beams. The characteristics of the accelerators heads of the Novac7 and Liac are different compared to conventional electron accelerators. The aim of this work was to investigate the specific characteristics of the Novac7 and Liac electron beams using the Monte Carlo method. The Monte Carlo code BEAMnrc has been employed to model the head and simulate the electron beams. The Monte Carlo simulation was preliminarily validated by comparing the simulated dose distributions with those measured by means of EBT radiochromic film. Then, the energy spectra, mean energy profiles, fluence profiles, photon contamination, and angular distributions were obtained from the Monte Carlo simulation. The Spencer-Attix water-to-air mass restricted collision stopping power ratios ( {\mathrm{s}}_{\mathrm{W},\text{air}} ) were also calculated. Moreover, the modifications of the percentage depth dose in water (backscatter effect) due to the presence of an attenuator plate composed of a sandwich of a 2 mm aluminum foil and a 4 mm lead foil, commonly used for breast treatments, were evaluated. The calculated {\mathrm{s}}_{\mathrm{W},\text{air}} values are in agreement with those tabulated in the IAEA TRS-398 dosimetric code of practice within 0.2% and 0.4% at {\mathrm{z}}_{\text{ref}} (reference depth in water) for the Novac7 and Liac, respectively. These differences are negligible for practical dosimetry. The attenuator plate is sufficient to completely absorb the electron beam for each energy of the Novac7 and Liac; moreover, the shape of the dose distribution in water strongly changes with the introduction of the attenuator plate. This variation depends on the energy of the beam, and it can give rise to an increase in the maximum dose in the range of 3%–9%. PACS number: 87.56.-v

Since Favaudon's paper of 2014, there has been an increasing interest in FLASH radiotherapy. The FLASH modality could represent a breakthrough in radiation oncology; nevertheless, it brings new scientific and technological challenges. Currently, one of the main limits the scientific community has to cope with is the lack of a common technological platform to experiment with. Considering this framework, the possibility of readapting existing linac platforms to produce a FLASH beam is particularly attractive and different attempts have been already made. The purpose of this article is to illustrate how it is possible to transform a dedicated Intra Operative Radio Therapy (IORT) mobile linac into a FLASH research machine. Compared to the modification required by a standard medical linac, such transformation is easier, does not affect the machine settings and can be rapidly performed by the final user. NOVAC 7 is an IORT linac which can reach a maximum dose-per-pulse up to 13 cGy/pulse (average dose rate 39 Gy/min); such dose rate can be significantly increased by modifying the collimation system. Four different Source Surface Distance (SSD) can be obtained: - Clinical reference configuration; - Upper applicator only (SSD 50 cm); - Monitor chambers housing only (SSD 7 cm); - Dismounted monitor chambers (SSD 1.6 cm). The fourth configuration allows reaching values of dose-per-pulse up to around 18 Gy/pulse and dose rates up to around 500 Gy/s, at a Pulse Repetition Frequency (PRF) of 30 Hz. The other three configurations can be obtained without using any tool and without changing NOVAC settings, until reaching a FLASH dose rate in the third configuration. For FLASH configurations, relative and absolute dosimetric characterization of the beam were performed using radiochromic films EBT3. NOVAC7 transformed in FLASH mode can be used both for dosimetric testing and characterization of detectors and for radiobiological studies on cells and organoids, offering a wide range of dose-per-pulse, from 3 cGy/pulse up to 18 Gy/pulse; dose rates correspondingly change from 3 cGy/s up to 540 Gy/s.

Ultra-high dose rate (UHDR) beams for FLASH radiotherapy present significant dosimetric challenges. Although novel approaches for decreasing or correcting ion recombination in ionization chambers are being proposed, applicability of ionimetric dosimetry to UHDR beams is still under investigation. Solid-state sensors have been recently investigated as a valuable alternative for real-time measurements, especially for relative dosimetry and beam monitoring. Among them, Silicon Carbide (SiC) represents a very promising candidate, compromising between the maturity of Silicon and the robustness of diamond. Its features allow for large area sensors and high electric fields, required to avoid ion recombination in UHDR beams. In this study, we present simulations and experimental measurements with the low energy UHDR electron beams accelerated with the ElectronFLASH machine developed by the SIT Sordina company (IT). The response of a newly developed 1 × 1 cm² SiC sensor in charge as a function of the dose-per-pulse and its radiation hardness up to a total delivered dose of 90 kGy, was investigated during a dedicated experimental campaign, which is, to our knowledge, the first characterization ever done of SiC with UHDR-pulsed beams accelerated by a dedicated ElectronFLASH LINAC. Results are encouraging and show a linear response of the SiC detector up to 2 Gy/pulse and a variation in the charge per pulse measured for a cumulative delivered dose of 90 kGy, within ±0.75%.

FLASH-radiotherapy delivers a radiation beam a thousand times faster compared to conventional radiotherapy, reducing radiation damage in healthy tissues with an equivalent tumor response. Although not completely understood, this radiobiological phenomenon has been proved in several animal models with a spectrum of all kinds of particles currently used in contemporary radiotherapy, especially electrons. However, all the research teams have performed FLASH preclinical studies using industrial linear accelerator or LINAC commonly employed in conventional radiotherapy and modified for the delivery of ultra-high-dose-rate (UHDRs). Unfortunately, the delivering and measuring of UHDR beams have been proved not to be completely reliable with such devices. Concerns arise regarding the accuracy of beam monitoring and dosimetry systems. Additionally, this LINAC totally lacks an integrated and dedicated Treatment Planning System (TPS) able to evaluate the internal dose distribution in the case of in vivo experiments. Finally, these devices cannot modify dose-time parameters of the beam relevant to the flash effect, such as average dose rate; dose per pulse; and instantaneous dose rate. This aspect also precludes the exploration of the quantitative relationship with biological phenomena. The dependence on these parameters need to be further investigated. A promising advancement is represented by a new generation of electron LINAC that has successfully overcome some of these technological challenges. In this review, we aim to provide a comprehensive summary of the existing literature on in vivo experiments using electron FLASH radiotherapy and explore the promising clinical perspectives associated with this technology.