Researchers from the ICO (Institut de Cancérologie de l’Ouest), Subatech laboratory and GIP ARRONAX have been collaborating for years to better understand the FLASH effect observed during external irradiation of living tissue at ultra-high dose rate (UHDR) and which could be used as a new therapeutic modality.

External radiation therapy uses ionizing radiation to destroy cancer cells while limiting the side effects on surrounding healthy cells. The total dose of radiation delivered in successive sessions is prescribed to achieve the best compromise between these two effects. The conventional dose rates currently used for these treatments are around a few Gy/min.

A new radiotherapy modality, known as ultra-high dose rate (UHDR), is currently under study. It is based on the FLASH effect, a phenomenon that has been observed on several occasions in preclinical work on animals when the dose is delivered at more than 40 Gy/s, i.e. the equivalent of 2400 Gy/min, in the form of very short and repeated pulses. This means that the dose delivered is identical, only the way of delivering it is modified. Under these irradiation conditions, the efficacy on the tumor is maintained but the toxicity on the surrounding tissues decreases. However, the occurrence of this effect is not systematic, which suggests that some conditions must be combined for it to occur. But it is not yet clear what these conditions are.

The FLASMOD project : a multidisciplinary approach within Arronax Nantes

Do beam settings have an impact? What are the mechanisms at work, in terms of physicochemical and biological reactions, when the FLASH effect occurs? The ecosystem in Nantes, made up of the GIP ARRONAX (accelerator and instrumentation teams), the Subatech laboratory (PRISMA and radiochemistry teams, radiolysis group) and the ICO (radiotherapy and medical physics departments, radiobiology team), united within Arronax Nantes, offers a privileged setting for answering these questions and contributing to a better understanding of the FLASH effect.

Work published in 2019 led to the development of a switch to change the flow mode (conventional vs. UHDR) of the Arronax cyclotron beam: a pulsing system allowing the structure of the irradiation pulses to be changed from a few microseconds to a few seconds (publication here). This device, set up at GIP ARRONAX, makes it possible to study the effect of the beam structure (number, duration, intensity of pulses) on the occurrence or non-occurrence of the FLASH effect, for the high-energy proton or alpha beams available at Arronax.

A dosimetry system adapted to UHDR has also been designed and set up at the end of the beam line at Arronax, allowing beam dosimetry measurements, off-line at least (publication here). Work by physicists in Nantes has also validated the Monte Carlo simulation model for dose calculation, including in complex environments in mice (publication here).

Enquête in vivo

The Subatech laboratory’s radiolysis team has demonstrated a significant decrease in the production of H2O2 in water under UHDR irradiation compared to conventional mode (publication here). Is this related to a lower concentration of OH° radicals available for chemical reactions under UHDR conditions, as suggested by the work of another team? To explore this hypothesis, it plans on measuring the production of different chemical species in an aqueous medium (H2O2, OH°, aqueous electrons) thanks to a new irradiation device currently under development at GIP ARRONAX.

It is now time for radiobiology studies to better understand the in vivo phenomena. The Nantes teams are working on zebrafish eggs and are observing changes in the development of the embryo as a result of different doses delivered at conventional rates or in UHDR. The first results are currently under study. Other research will follow, requiring the construction of an irradiation table adapted for mice compatible with the XRAD225Cx system installed at the ICO.

Collaborations are also underway with researchers in medical physics and applied physics at the LPC in Clermont-Ferrand on the simulation aspects of the irradiated medium’s response on a microscopic scale with the G4-DNA software, as well as with Belgian teams from the universities of Namur and Louvain and the IBA company, which manufactures the Arronax cyclotron, in order to develop a beam profiler that operates in UHDR and to study the beam parameters in UHDR for patient treatment.


Contacts :

ICO : Grégory Delpon
GIP ARRONAX : Charbel Koumeir
Laboratoire Subatech : Guillaume Blain