Abstract Body

There is currently high interest in new radiotherapy approaches employing significantly higher dose rates than used in conventional practice, where radiation is typically delivered at a few Gy/minutes. This follows from the recent demonstration of the normal tissue sparing effects of radiation delivered at high-dose rate (10s to 1000s Gy/s), which have highlighted the promise of the so-called FLASH approach as the next step towards an advanced and more effective form of cancer radiotherapy. While this is motivating a large number of in-vitro and in-vivo studies aimed to clarify the mechanisms behind the FLASH effect, it has also revived a broader fundamental interest in the investigation of the dose rate dependency of the biological effects of radiation.

Amongst existing radiation sources, particle beams accelerated by high power lasers provide unique capabilities for these studies, as the particles are emitted in intrinsically ultrashort and very bright bursts. Of particular relevance are laser-driven ion beams: these are typically accelerated on picosecond timescales, resulting in distinctive properties, which differ strongly from those of the beams produced by conventional Radio-Frequency (RF) accelerators. A number of experiments have demonstrated that, with a suitable selection and transport system, it is possible to deliver to a sample multi-Gy doses in single nanosecond, or sub-ns, pulses, i. e. at dose rates exceeding 10⁹ Gy/s, which allow extending radiobiological investigations to new, extreme irradiation regimes.

The talk will review the main laser-based acceleration mechanisms as well as the beam properties which have been demonstrated in experiments. While the so-called Target Normal Sheath Acceleration mechanism is the established method for delivering proton beams and has been used in numerous irradiation experiments, opportunities exist for accelerating and delivering other species, e.g. carbon, through emerging mechanisms such as Radiation Pressure Acceleration, which act on the bulk of an ultrathin foil.

We will also discuss the results of experimental campaigns where the laser-driven ions have been used to irradiate biological samples at ultra-high dose rate, and to highlight, through a number of suitable assays, similarities and differences with known biological effects at conventional dose rates. Data dependencies on dose, dose-rate, particle LET, cell type, sample dimensionality and oxygenation highlight a complex scenario which challenges established understanding and requires new hypotheses and models.

Abstract Body

There is currently high interest in new radiotherapy approaches employing significantly higher dose rates than used in conventional practice, where radiation is typically delivered at a few Gy/minutes. This follows from the recent demonstration of the normal tissue sparing effects of radiation delivered at high-dose rate (10s to 1000s Gy/s), which have highlighted the promise of the so-called FLASH approach as the next step towards an advanced and more effective form of cancer radiotherapy. While this is motivating a large number of in-vitro and in-vivo studies aimed to clarify the mechanisms behind the FLASH effect, it has also revived a broader fundamental interest in the investigation of the dose rate dependency of the biological effects of radiation.

Amongst existing radiation sources, particle beams accelerated by high power lasers provide unique capabilities for these studies, as the particles are emitted in intrinsically ultrashort and very bright bursts. Of particular relevance are laser-driven ion beams: these are typically accelerated on picosecond timescales, resulting in distinctive properties, which differ strongly from those of the beams produced by conventional Radio-Frequency (RF) accelerators. A number of experiments have demonstrated that, with a suitable selection and transport system, it is possible to deliver to a sample multi-Gy doses in single nanosecond, or sub-ns, pulses, i. e. at dose rates exceeding 10⁹ Gy/s, which allow extending radiobiological investigations to new, extreme irradiation regimes.

The talk will review the main laser-based acceleration mechanisms as well as the beam properties which have been demonstrated in experiments. While the so-called Target Normal Sheath Acceleration mechanism is the established method for delivering proton beams and has been used in numerous irradiation experiments, opportunities exist for accelerating and delivering other species, e.g. carbon, through emerging mechanisms such as Radiation Pressure Acceleration, which act on the bulk of an ultrathin foil.

We will also discuss the results of experimental campaigns where the laser-driven ions have been used to irradiate biological samples at ultra-high dose rate, and to highlight, through a number of suitable assays, similarities and differences with known biological effects at conventional dose rates. Data dependencies on dose, dose-rate, particle LET, cell type, sample dimensionality and oxygenation highlight a complex scenario which challenges established understanding and requires new hypotheses and models.

Background and Aims

Dosimetry for FLASH radiotherapy, VHEE radiotherapy as well as for laser-driven beams cause significant metrological challenges due to the ultra-high dose rates and pulsed structure of these beams, in particular for real time measurements with active dosimeters. It is not possible to simply apply existing Codes of Practice available for dosimetry in conventional external radiotherapy here. However, reliable standardized dosimetry is necessary for accurate comparisons in radiobiological experiments, to compare the efficacy of these new radiotherapy techniques and to enable safe clinical application. UHDpulse aims to develop the metrological tools needed for reliable real-time absorbed dose measurements of electron and proton beams with ultra-high dose rate, ultra-high dose per pulse or ultra-short pulse duration.

Methods

Within UHDpulse, primary and secondary absorbed dose standards and reference dosimetry methods are developed, the responses of available state-of-the-art detector systems are characterised, novel and custom-built active dosimetric systems and beam monitoring systems are designed, and methods for relative dosimetry and for the characterization of stray radiation are investigated.

Results

Prototypes of different active dosimetry systems show promising results for real-time dosimetry for particle beams with ultra-high pulse dose rates. The results of the UHDpulse project will be the input data for future Codes of Practice.

Conclusions

A brief overview of the progress in the UHDpulse project and the involved institutions will be given.

Acknowledgement: This project 18HLT04 UHDpulse has received funding from the EMPIR programme co-financed by the Participating States and from the European Union’s Horizon 2020 research and innovation programme.

Background and Aims

Advancement in accelerator technology has led to the development of systems capable of generating particle beams with ultra-high dose rates per pulse, facilitating investigations of radiation therapy modalities characterized by dose deliveries exceeding several hundred Gy/s. The FLASH effect is induced at rates greater than 40 Gy/s, subsequently reducing undesired healthy tissue damage, whilst maintaining comparable tumour control to conventional techniques. Further, laser-driven acceleration of charged particle beams produced with compact “plasma accelerators” are characterized by even higher dose rates per pulse (up to 10⁹ Gy/s) at quasi-instantaneous irradiations.

Methods

Despite this, dosimetry of these beams has proven to be technically challenging, requiring the development of novel strategies to replace already established methods for conventional radiotherapy. As such, a small portable graphite calorimeter has been developed and modified at National Physical Laboratory (NPL) to conduct absolute dose measurements of high dose rate per pulse proton beams.

Results

Proof of principle measurement of the absorbed dose of laser-driven proton beams have been carried out with this device, representing the first ever based on calorimetry techniques. Energetic proton beams of up to 40 MeV were produced using the VULCAN petawatt laser system of the Central Laser Facility of the Rutherford Appleton Laboratory. Doses per pulse of up to 3 Gy were measured, with negligible electromagnetic pulse (EMP) contribution to the signal.

Conclusions

This project 18HLT04 UHDpulse has received funding from the EMPIR programme co-financed by the Participating States and from the European Union’s Horizon 2020 research and innovation programme.

Background and Aims

Laser-driven ion acceleration is attracting significant interest in the radiobiological community, as it allows to deliver dose in ultrashort bursts with high dose rates (10⁹-10¹⁰ Gy/s), opening up for investigation novel regimes of radiobiology. These studies require the implementation of bespoke and innovative arrangements for beam delivery and dosimetry.

Methods

The PW VULCAN and GEMINI laser systems at the Rutherford Appleton laboratory were used to generate, respectively, proton and carbon ion bunches. 35 MeV protons and 10 MeV/u carbon ions were magnetically selected and used to irradiate 2D and 3D biological samples, in single exposures. The 2D-samples were plated on a dish and placed inside a vertical holder while 3D models (Glioblastoma neurospheres) were immersed in cell culture medium and placed at the bottom of a thin-walled 3 mm diameter polypropylene tube. Dosimetry was performed on every shot by employing previously calibrated, unlaminated EBT3-Radio-Chromic Film (RCF) for carbon ion dosimetry, while standard EBT3-RCF was used for the proton measurements.

Results

Doses in the 1-5 Gy range with 10% dose variation over 3x3 mm² surface, were delivered to the cells and measured. The proton depth-dose profile along the 3 mm thick tube was evaluated with an EBT3-RCF stack phantom, showing a 5% dose uniformity along the whole tube thickness.

Conclusions

The irradiation and dosimetry approach enabled controlled irradiation of 2D and 3D samples, with a shot-to-shot precise dose determination.

Acknowledgements

This project 18HLT04 UHDpulse has received funding from the EMPIR programme co-financed by the Participating States and from the European Union’s Horizon 2020 programme.

Background and Aims

The normal tissue sparing effects of FLASH radiotherapy have revived interest in ultra-short pulse, ultra-high dose rate (UHDR) radiobiology, with several recent FLASH and UHDR pre-clinical studies using low-LET radiation. High power lasers enable the delivery of Gy level carbon dose at dose rates > 10⁹ Gy/sec, opening up to investigation the still unknown radiobiology of UHDR, high-LET radiation

Methods

At the Gemini Laser of the Central Laser Facility, Rutherford Appleton Laboratory, Glioblastoma stem like cells (GSCs) were exposed to 1 Gy of 10 MeV/n carbon ions in single pulses of ~ 400-picosecond duration, at a dose rate of 2.5 x10⁹ Gy/sec. Carbon ions were accelerated by focussing 45 fs, 6 J laser pulses onto 10-25 nm thick carbon foils at intensity ~ 6 10²⁰ W/cm². We used the 53BP1 foci assay to study carbon ions induced DNA damage and compared the results with 225kVp X-rays induced DSB damage in the GSCs.

Results

Laser-driven carbon ions induced complex DNA DSB damage, as seen through persistent 53BP1 foci (11.3 ± 0.5 foci per cell) at 24 hrs, compared to X-rays where the foci levels reduced to near the background levels. The relative foci induction values of laser-driven carbon ions normalized to X-rays was found to be 5.75 ± 0.51

Conclusions

Overall, this is the first study to report the radiobiological effectiveness of laser-accelerated carbon ions, demonstrating a method to accelerate and deliver high LET carbon ions in radioresistant GBM stem cell models in single ultrashort single sub-nanosecond pulses.