Research team
Expertise
The FLASH effect, obtained with radiation therapy at ultra-high dose rate (FLASH-RT), is defined as sparing normal tissues while maintaining the tumour effect compared to conventional dose-rate radiation therapy (CONV-RT). It has been observed after exposure of biological tissues to electrons, X-rays and protons. As the technology to transfer FLASH radiation therapy (FLASHRT) with X-rays and protons into the clinics is still in development, and facing a high number of challenges, FLASH-RT using electrons is the logical choice to being used primarily for clinical applications. Current linear accelerators producing electrons for FLASH allow to reach superficial tumours as well as deeper-seated tumours in the context of Intra-Operative electron Radiation Therapy (IOeRT) applications. Both external beam and IOeRT are used for the treatment of breast cancer (Harbeck 2019; Fastner 2020). At the Iridium Kankernetwerk in Antwerp, one of the 3 Belgian IOeRT linear accelerators is available for treatment of breast cancer patients both for a boost to the primary tumour bed (for high-risk patients) and for single-dose partial breast irradiation (for low-risk patients) (Fastner 2020; Bartelink 2015, Machiels 2020). This forms an ideal matrix for investigating the capacities of FLASH-RT to control the tumour while avoiding the development of normal tissue toxicities in the irradiated volume, representing a challenging opportunity to improve the therapeutic management of breast cancer. Combining our existing experience with IOeRT for breast cancer patients with the installation of the ElectronFlash research machine paves the way to compare conventional with FLASH dose rates for radiation therapy using IOeRT irradiators. This thrid step of the proposed research programme, the introduction in the clinic, is expected to become feasible in the course of 2023 with the installation of world wide’s first CE-marked IOeRT machine for clinical use, that is capable of delivering both conventional and FLASH dose rates. Thereby, our research project aims at bringing FLASH dose rate radiation therapy as fast as possible from the bench to the bedside: • WP1: Investigation of the underlying mechanisms will be performed with a combination of in vivo and in vitro experiments. The FLASH effect has been described to be partially dependent on tissular oxygen tension (Montay-Gruel 2019; Spitz 2019; Petersson 2020, Adrian 2020; Hughes 2020) and only observable in vitro when cells are cultured in physiological oxic conditions (i.e., under 4-5% O2). In vitro assays, using 5 different cell lines maintained in spheroids, will be performed to investigate differential radiation induced cell death and DNA damage response after FLASH-RT and CONV-RT. Biological samples from WP2 will also be used to assess immune infiltration in both tumour and normal tissues along with tumour cell killing. • WP2: Simultaneously, we will use a preclinical mouse model to investigate the impact of FLASH dose rates, as compared to conventional dose rates, on breast cancer treatment. Simultaneously, we will compare normal tissue toxicity on the skin, soft tissue, lungs and heart between FLASH and conventional dose rate radiation therapy. Finally, we will investigate innovative combinations in the field of FLASH research with tamoxifen/letrozole, as this influences cosmetic outcome after CONV-RT.
FLASH radiation therapy to improve the therapeutic management of breast cancer by reducing radiationinduced skin, soft tissue, lung and heart toxicities.
Abstract
FLASH-RT, based on ultra-high dose rate irradiation (instantaneous dose rate above 104 Gy/s), recently became a hot topic in the field of radiation oncology. Several studies have recently shown that classical pathogenic patterns observed in normal tissues exposed to radiation delivered at conventional dose rate radiation therapy (CONV-RT) were not induced by single fractions of FLASH-RT, collective observations that we have since defined as the "FLASH effect". Published data forms a growing body of literature, documenting the marked normal tissue sparing found in multiple tissues (brain, lung, skin, gut) and in multiple mammalian species (mouse, cat, pig, rat) subjected to FLASH-RT (Favaudon 2014; Montay-Gruel 2017, 2018, 2020; Vozenin 2018; Alaghband 2020; Wilson 2020). These findings, along with data showing fully conserved anti-tumour efficacy and the first human trial (albeit for skin cancer) (Bourhis 2019, 2020) point to the exciting clinical promises of delivering FLASHRT in a large number of tumour sites. This previous research highlights the feasibility of translating preclinical studies into clinical trials for the treatment of cancers while limiting normal tissue toxicities. Therefore, the Iridium Kankernetwerk and the University of Antwerp is the first radiation oncology centre in Belgium, and the second in the world, to be equipped with the ElectronFlash irradiator developed by S.I.T. (Sordina IORT Technologies S.p.A., Italy - hereafter "S.I.T.") and thereby able to deliver ultra-high dose rate irradiation to attain the FLASH effect in preclinical circumstances. Currently, S.I.T. is developing a new accelerator for IOeRT, capable to deliver both CONV-RT and FLASH-RT. We should be the first centre in the world where this revolutionary machine for clinical applications will be installed, in the course of 2023, including CE-marking for clinical use. The preclinical research described in this project will consist in developing and using in vitro and in vivo tumour models to validate and optimize the treatment of breast tumour types using FLASH-RT. Therefore, our project aims at investigating the effect of FLASH-RT (compared to CONV-RT) on breast cancer and on radiation-induced skin, soft tissue, lung and heart toxicities. Up to now, while FLASH-RT has been found to prevent the development of radiation-induced toxicities on many different organs while keeping a good antitumour effect, no study has focused on its use for breast cancer treatment. The preclinical data obtained from this project is essential to ensure a safe and efficacious transfer of FLASH-RT to clinical breast cancer practice at the Iridium Kankernetwerk and University of Antwerp. Recent studies have suggested that the optimal FLASH effect was obtained with single dose exposures and with hypo-fractionated regimens (Bourhis 2019; Montay-Gruel 2020). This is compatible with IOeRT in both partial and whole breast irradiation settings, as this entails routinely the delivery of a single high dose of radiation (21 Gy for partial breast irradiation in low-risk patients; 9 Gy for a boost combined with routine whole breast irradiation in high-risk patients.Researcher(s)
- Promoter: Meijnders Paul
- Co-promoter: Wouters An
Research team(s)
Project website
Project type(s)
- Research Project