FLASH-DC

The FlashDC - Flash Dosimeter Counter Project, funded by the Lazio Region, Italy (Public Notice of Research Groups 2020 POR FESR LAZIO 2014-2020), is part of the research for Life Science: it belongs to the biomedical sector of medical devices for research and hospital use devoted to Health System improvement. It promotes better cancer treatment minimizing the onset of secondary cancers, with the consequent increase in the quality of life of patients and the reduction of costs for the National Health Service. During the two years of the project, an innovative dosimeter monitor will be developed for the characterization of the Flash radiotherapy beams.

According to the International Agency for Research on Cancer the incidence of tumours, in Italy, in 2018 was the 2.8% of world cases (for a total of more than 400,000 new cases, with a mortality of about 40%, https: //gco.iarc.fr/today). Despite the mortality in Europe in the last two years was plagued by the Covid19, the huge number of pandemic correlated deaths is still a factor ten less than the annual number of cancer deaths. This is one of the reasons why cancer research has been declared as one of the 5 specific missions of the next EU research and innovation program, Horizon Europe (2021-27). Surgery, chemotherapy and conventional radiotherapy can intervene, often in combination, in only 65% ​​of cases, leaving an important number of patients without the possibility or hope of recovery. The criticality of the incurable cases is due to the position of the tumour in the patient, close to organs at risk (OaR), and/or to the radio-resistance of the cancer. In a radiotherapy treatment beams of photons (or electrons) deposit energy on cancer-causing tissues, destroying them (dose = energy absorbed per unit of mass, [Gy]). The spatial combination of different therapeutic beams allows optimizing the treatment preserving the surrounding healthy tissues as much as possible (Treatment Planning System-TPS). Despite the increasing improvement of the control of the treatment there is an intrinsic limitation to the technique due to the morphology of the dose distribution. Photons and electrons produce a release of energy that expands in the patient and passes through it completely, thus inevitably also irradiating the adjacent tissues. Since in the case of OaR the dose must be kept below specific limits, the treatment of a very large number of tumours cannot be planned.

FLASH Radiotherapy (FLASH-RT) is a novel technique that consists in administering the entire radiation in a highly concentrated time, i.e. at dose rates well above conventional ones (by a factor 10). Various pre-clinical in vivo experiments carried out on different animals and organs, using electron beams of 4-6 MeV at a dose rate higher than 40 Gy per s (for a total irradiation duration of less than 200 ms), showed a reduction of side effects on healthy tissues preserving the therapeutic efficacy on tumour tissue. The results attracted considerable attention in the scientific and medical community for their potential clinical applications: the possibility to increase the dose without increasing the damage to neighbouring tissues would allow to effectively treat those tumours otherwise radio-resistant and/or in close to OaR. The number of scientific papers relating to FLASH-RT published is growing indicating the increasing interest of the medical and scientific community. The number of Patents is also increasing: to date there are more than one hundred thousand of which eleven thousand in Europe (Source www.scopus. com). The main advantages of FLASH-RT over conventional radiation therapy are the tissue preservation (it enhances the differential effect between tumours and healthy tissues and organ), the time (it delivers doses within an extremely short irradiation time) and the the fact that the dose is iso-effective compared to conventional RT dosage, reducing normal tissue toxicity and side effects.The social impact of such a technique is incalculable; however there are still many open problems to be addressed before using the FLASH-RT in clinical practice. Although several possible explanations have been proposed, the radiobiological mechanism underlying the FLASH effect is still unknown. Furthermore, the dependence on the LET (Linear Energy Transfer) of the radiation used is still unknown since most of the experiments were performed with low-energy electron beams. There are technical/engineering difficulties in obtaining beams of sufficient intensity to achieve the FLASH effect and so far only the dependence on the average dose rate and the duration of the entire irradiation has been clearly observed. The role of the dose per pulse, the instantaneous dose per pulse (dose per pulse divided by the duration of the pulse), the duration of the pulse and the frequency are to be understood. The accelerators used up to now for FLASH in vivo experiments are electron accelerators designed for industrial use or modified medical accelerators, where the diffuser filters and the monitor chambers have been disassembled and mechanically removed from the beam path. Therefore such accelerators are unable to monitor the beam parameters in real time and provide accurate and reproducible outputs.  Furthermore dosimetry (i.e. the measurement of the dose associated with the beams used) is particularly critical because of the instrumental saturation of the clinical devices used in standard radiotherapy. In the papers published so far, the dosimetry was performed using independent dose-rate dosimeters, in most cases radiochromic films that do not have the same accuracy as other detectors, do not provide dosimetric information online and are unable to control any changes in the output during the experiment and they cannot measure the characteristics of the beam pulse by pulse but they can only provide integrated information. Due to all these limitations and to the problems in obtaining quantitative radiobiological data from in vivo experiments the dependencies of the FLASH effect on various parameters of the beams are not yet defined.

Contrary to conventional dosimeters the FlashDC project aims to develop an innovative dosimeter-beam monitor, based on a different physical principle: the air fluorescence. This effect allows both to minimize the impact of the detector on the beam line, thus preserving the best irradiation conditions for the patient, and, to develop an instrument capable to perform pulse-by-pulse monitor with an unsaturated signal. The project clearly fits into the context of the objectives of the national programs and of the European community for research and innovation in the biomedical field, with particular attention to the oncological medicine sector, currently in third place among the social challenges (Horizon 2020) related to priority issues for AdS Life Sciences. The final goal of the FlashDC project is to develop a dosimetry technique for the characterization of Flash radiotherapy beams at all energies, intensities and types of ionizing particles (electron, proton, ions). In the event of success, it is also intended to design and patent, in collaboration with the company SIT-SORDINA, a dosimeter for commercial purposes. In terms of intermediate objectives, first a prototype will be developed to demonstrate the technique. Then the prototype will be characterized with electron beams at Flash intensity and energy (5-10 MeV) at the SIT-SORDINA (Pomezia, Rome). On success the collaboration will move to the characterization of the prototype at higher energies at the Institut Curie-Center de Recherche et Traitement du Cancer (Orsay - Paris, France).

FlashDC will be an example of technological transfer; the applied physics research team in collaboration with the world of industry will bring an innovative device to the operational and commercial environment. To date the design idea is at an intermediate level and the experimental concept is being validated. With the FlashDC project the collaboration will test the prototype system in an industrially relevant (eg. SIT-SORDINA) and operational (eg. Curie Institute) environment, bringing the level of Technology Readness to a value of 6- 7. FlaschDC so will improve the connection between industries (technological companies) and the world of innovation and research: on the basis of the results, at the end of the project, the possibility to bring the validation of the system and its production at commercial level will be evaluated.

• Sapienza Università di Roma
• Centro Ricerche Enrico Fermi
• INFN
• S.I.T. – Sordina IORT Technologies S.p.A.