Revisiting the ultra-high dose rate effect: implications for charged particle radiotherapy using protons and light ions

Abstract

Objective: To reinvestigate ultra-high dose rate radiation (UHDRR) radiobiology and consider potential implications for hadrontherapy. Methods: A literature search of cellular UHDRR exposures was performed. Standard oxygen diffusion equations were used to estimate the time taken to replace UHDRRrelated oxygen depletion. Dose rates from conventional and novel methods of hadrontherapy accelerators were considered, including spot scanning beam delivery, which intensifies dose rate. Results: The literature findings were that, for X-ray and electron dose rates of around 10 9 Gy s -1 , 5-10 Gy depletes cellular oxygen, significantly changing the radiosensitivity of cells already in low oxygen tension (around 3 mmHg or 0.4 kPa). The time taken to reverse the oxygen depletion of such cells is estimated to be over 20-30 s at distances of over 100 mm from a tumour blood vessel. In this time window, tumours have a higher hypoxic fraction (capable of reducing tumour control), so the next application of radiation within the same fraction should be at a time that exceeds these estimates in the case of scanned beams or with ultra-fast laser-generated particles. Conclusion: This study has potential implications for particle therapy, including lasergenerated particles, where dose rate is greatly increased. Conventional accelerators probably do not achieve the critical UHDRR conditions. However, specific UHDRR oxygen depletion experiments using proton and ion beams are indicated.

The radiobiology of laser-driven particle beams: focus on sub-lethal responses of normal human cells

“…several orders of magnitude larger than the ones used in the current therapeutic regimes [9]. While laser-driven particle beams can be thus seen as a valuable probe to investigate the core mechanisms of radiation action at the sub-nanometer and femtosecond scales [10,11], it has been suggested that the extreme spatio-temporal nature of laser-driven particle beams may ensue unknown biological responses [7,12,13]. Hence, ultra-fast high-energy particle radiobiology will have to ascertain whether and to what extent cellular radiosensitivity is influenced by such peculiar irradiation regimes.…”

Laser‐driven radiation: Biomarkers for molecular imaging of high dose‐rate effects

“…The molecular effects of radiation pulses delivered to cells on these timescales are anticipated to offer new therapeutic promises. 38 Decreases in tumor radiosensitivity by transient oxygen depletion following a short-pulse irradiation 39 are an issue to be considered in high dose-rate radiation experiments. The time to reverse oxygen depletion within tumors is estimated to be> 20 s at distances of about 100 µm from a tumor blood vessel.…”

Towards Laser Driven Hadron Cancer Radiotherapy: A Review of Progress

“…The presence of oxygen is known to enhance cell lethality by a factor of about 3 for low LET radiation [106]. This enhancement is probably due to the fact that DNA radicals readily react with oxygen to generate biologically relevant DNA damage [107].…”

“…At ultra-high dose rates (~10 9 Gy/second or more) for low LET radiation this oxygen effect is evident in hypoxic tissue, as several Gy dose levels deplete the oxygen level at such dose rates. Although oxygen is easily accessible to single monolayer cells, oxygen recovery to regions of diffusion-related hypoxia, which are often observed in a relatively small proportion of tumor tissues, can require significant time (several seconds for tissues having distances of more than 100 μm from a tumor blood vessel) [106]. This means that the efficiency of cell inactivation in a tumor needs to be optimized or improved with the mode of irradiation featuring breaks (brief time intervals with no irradiation) of adequate duration (~seconds) such that all cells in a tissue are accessible to oxygen.…”