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Paul Meijnders

  • Research 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.
  • Disciplines:Cancer therapy
  • Research techniques:Biological changes induced by conventional and FLASH radiotherapy in 3D breast spheroids representative of the breast cancer molecular subtype spectrum. • To confirm the absence of differences in radiosensitivity/resistance between FLASH and CONV radiation therapy of a panel of 3D breast cancer spheroids derived from 5 different breast cancer cell lines; • To relate possibly encountered differences in radiosensitivity to differences in biological events; • To enhance and ensure a successful transfer of preclinical data to clinical applications of FLASH radiation therapy Deliverables: • A clear overview of the biological effects of CONV versus FLASH radiation therapy on 3D breast cancer spheroids (5 different cell lines). • Confirm that the biological effect of FLASH radiation therapy is at least not inferior to that of CONV radiation therapy. Milestones: • Validation of published in vitro findings in 3D tumour spheroids of several breast cancer lines, in order to enhance and ensure a successful transfer of FLASH radiation therapy to subsequent preclinical and clinical applications. In vivo investigation of FLASH-RT efficacy on breast cancer and toxicity on normal tissues. • Investigate and optimise the antitumour effect of FLASH-RT on murine breast cancer models, alone and combined with systemic treatments • Evaluate the toxicity of FLASH-RT on the skin, soft tissue, lung and heart in the context of breast cancer treatment, alone or combined with systemic treatments (tamoxifen/letrozole). Clinical introduction of intra-operative FLASH radiation therapy for treatment of early-stage low-risk breast cancer patients. Partial breast irradiation is a standard treatment for early-stage low-risk breast cancer patients (Miranda 2019). Intraoperative radiation therapy with electrons is one of the approved technical modalities to give partial breast irradiation (Fastner 2020; Kaidar-Person 2020). Currently, in Antwerp this technique is delivered using a linear accelerator dedicated for intraoperative electron beam radiation therapy (Liac HWL, S.I.T.). The installation of the first clinical linear accelerator capable of delivering both conventional and FLASH dose rate electrons for intraoperative partial breast irradiation is expected for 2023. This will allow us to compare intraoperative electron partial breast irradiation for early-stage low-risk breast cancer patients using two different dose rates (CONV versus FLASH). • All consecutive patients who will be treated (with the currently available conventional dose rate Liac HWL linear accelerator) with intraoperative partial breast irradiation starting from January 2022 on will be invited to participate in a registration study. After signing informed consent, registration of patient-, tumour-, treatment- and outcome-related data will be performed, identical to what we will use for the treatment at FLASH dose rates. • Once the FLASH-machine becomes available for clinical use, expected during the course of 2023, patients who accept participation to this study will be treated using FLASH dose rate intraoperative radiation therapy, according to a set-up that is identical to that of conventional dose rate intraoperative radiation therapy, apart from the dose rate. In parallel, patients who prefer not to participate to the study with FLASH dose rate intraoperative radiation therapy (and treated with conventional dose rate) will be invited to participate to a registration study in which identical tumour-, treatment and outcome-related factors will be collected. Study design: • Patient accrual: patients will be invited to participate in a registration of their patient-, tumour-, treatment- and outcome-related data. After signed informed consent, patients will be treated with intraoperative partial breast irradiation according to international guidelines and our current protocol (Fastner 2020; Machiels 2020). From the moment on that the new FLASH machine is installed and approved for clinical use, patients will be invited to participation in the feasibility study for intraoperative partial breast irradiation at FLASH dose rates. • Safety: the first 3 months a maximum of 1 patient per week will be treated at FLASH dose rates. After treating the first 5 patients, an evaluation of all data up to the follow up period of 3 months will be made and compared to those of the patients treated with conventional dose rate. In the absence of increased side effects, accrual of patients treated with FLASH dose rate will be continued. • Final evaluation in the framework of this study: all patients treated with FLASH dose rate at the end of December 2025 will be analysed and compared to the patients treated with conventional dose rate. With an accrual of 2 patients per month (eligible and agreeing to participate), an interruption for the safety evaluation, and unexpected delays, a total of at least 25 patients is expected to be eligible for evaluation. A matched-pair analysis using the patients treated with conventional dose rate (estimated to be at least 75, resulting in 3 control patients for each FLASH-treated patient) will be performed. • Remark: thereafter, patients will continue the scheduled follow-up for confirming the first results that can be derived from this study. • Follow-up: all patients will be seen at 3, 6, 12, 18, 24, 30, 36, 48, 60 months from the date of study entry.
  • Users of research expertise:researchers interested in FLASH radiotherapy: cooperation with the research group or use of the FLASH machine for research projects