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.

Purpose FLASH radiotherapy (RT) is an emerging technique in which beams with ultra‐high dose rates (UH‐DR) and dose per pulse (UH‐DPP) are used. Commercially available active real‐time dosimeters have been shown to be unsuitable in such conditions, due to severe response nonlinearities. In the present study, a novel diamond‐based Schottky diode detector was specifically designed and realized to match the stringent requirements of FLASH‐RT. Methods A systematic investigation of the main features affecting the diamond response in UH‐DPP conditions was carried out. Several diamond Schottky diode detector prototypes with different layouts were produced at Rome Tor Vergata University in cooperation with PTW‐Freiburg. Such devices were tested under electron UH‐DPP beams. The linearity of the prototypes was investigated up to DPPs of about 26 Gy/pulse and dose rates of approximately 1 kGy/s. In addition, percentage depth dose (PDD) measurements were performed in different irradiation conditions. Radiochromic films were used for reference dosimetry. Results The response linearity of the diamond prototypes was shown to be strongly affected by the size of their active volume as well as by their series resistance. By properly tuning the design layout, the detector response was found to be linear up to at least 20 Gy/pulse, well into the UH‐DPP range conditions. PDD measurements were performed by three different linac applicators, characterized by DPP values at the point of maximum dose of 3.5, 17.2, and 20.6 Gy/pulse, respectively. The very good superimposition of three curves confirmed the diamond response linearity. It is worth mentioning that UH‐DPP irradiation conditions may lead to instantaneous detector currents as high as several mA, thus possibly exceeding the electrometer specifications. This issue was properly addressed in the case of the PTW UNIDOS electrometers. Conclusions The results of the present study clearly demonstrate the feasibility of a diamond detector for FLASH‐RT applications.

Purpose: The electron linac ElectronFlash installed at Institut Curie (Orsay, France) is entirely dedicated to FLASH irradiation for radiobiological and pre-clinical studies. The system was designed to deliver an ultra-high-dose rate per pulse (UHDR) (above 106 Gy/s) and a very high average dose rate at different energies and pulse durations. A campaign of tests and measurements was performed to obtain a full reliable characterizations of the electron beam and of the delivered dose, which are necessary to the radiobiological experiments. Methods: A Faraday cup was used to measure the electron charges in a single RF pulse. The percentage depth dose (PDD) and the transverse dose profiles, at the energies of 5 MeV and 7 MeV, were evaluated employing Gafchromic films EBT-XD for two Poly-methylmethacrylate (PMMA) applicators with irradiation sizes of 30 mm and 120 mm, normally used for in vivo and in vitro experiments, respectively. The results were compared with Monte Carlo (MC) simulations. Results: The measurements were performed during a period of a few months in which the experimental set up was adapted and tuned in order to characterize the electron beam parameters and the values of delivered doses before the radiobiological experiments. The measurements showed that the dose parameters, obtained at the energy of 5 MeV and 7 MeV with different applicators, fulfill the FLASH regime, with a maximum value of an average dose rate of 4750 Gy/s, a maximum dose per pulse of 19 Gy and an instantaneous dose rate up to 4.75 ×106 Gy/s. By means of the PMMA applicators, a very good flatness of the dose profiles was obtained at the cost of a reduced total current. The flatness of the large field is reliable and reproducible in radiobiological experiments. The measured PDD and dose profiles are in good agreement with Monte Carlo simulations with more than 95% of the gamma-index under the thresholds of 3 mm/3%. Conclusions: The results show that the system can provide UHDR pulses totally satisfying the FLASH requirements with very good performances in terms of beam profile flatness for any size of the fields. The monitoring of electron beams and the measurement of the dose parameters played an important role in the in vivo and in vitro irradiation experiments performed at the Institut Curie laboratory.

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Intermittent claudication impairs functional status and quality of life in many patients by limiting walking capacity. The aim of this study was to evaluate the effects of a 4-week treatment with prostaglandin E1 (PGE1), a drug inducing vasodilation and inhibiting platelet aggregation, on improving functional status and health-related quality of life in patients with disabling intermittent claudication. Forty-two untrained outpatients (37 men and five women, mean age 64 +/- 8 years) with intermittent claudication,and maximum walking distance (MWD) of at least 50 and no more than 200 m on treadmill test (5% slope, 3 km/hr) were randomized to 4 weeks of double-blind treatment either with 60 mcg PGE1 daily given IV in 250 mL saline over a period of 2 hours (21 patients) or placebo (250 mL saline, 21 patients). Treatment-free follow-up was completed 8 weeks after the final infusion. Pain free walking distance (PFWD), MWD, and questionnaire evaluation were determined at baseline, after the 4-week treatment period, and at the end of the 8 weeks of the treatment-free follow-up period. After 4 weeks of treatment with PGE1 PFWD and MWD increased from 72 +/- 16 m to 135 +/- 33 m (+87%, p<0.001)and from 140 +/- 30 m to 266 +/- 62 m (+90%, p<0.001), respectively. Analysis of the Walking Impairment Questionnaire responses in the PGE1 group at 4 weeks demonstrated significant improvements in the walking impairment score (+19 percentage points, p<0.001), in the distance score (+25 percentage points, p<0.001), in the speed score (+24 percentage points, p<0.001), in the stair climbing score (+20 percentage points, p<0.001). The RAND survey responses showed improvements in physical function and bodily pain scores (+14 percentage points, p<0.001, and +15 percentage points, p<0.01, respectively). After the treatment-free follow-up period of 8 weeks, increases in PFWD and MWD were maintained (113 +/- 26 m, +57%, p<0.001, and 229 +/- 55 m, +63%, p<0.001, respectively). Similarly, at the end of the treatment-free follow-up, the walking impairment score (+16 percentage points, p<0.001), the distance score (+23 percentage points, p<0.001), the speed score (+22 percentage points, p<0.001), the stair climbing score (+18 percentage points, p<0.001) as well as the RAND physical function and bodily pain scores (+10 percentage points, p<0.001, and +13 percentage points, p<0.01, respectively) were still increased compared with baseline. No change from baseline was found in all the target parameters in the placebo group after 4 weeks of treatment and at the end of the treatment-free follow-up period. These data show that a 4-week treatment with PGE1 improves functional status and quality of life as well as treadmill performance in patients with disabling intermittent claudication as compared with placebo-treated patients. The improvements are also maintained for a period of 8 weeks beyond the end of the treatment. Additional studies are needed to determine the duration of functional benefits after the end of treatment.

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