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Advancements in Particle Therapy Radiation Biology: Challenges and Prospects for Space and Cancer Research

Investigating low and high LET radiation effects, RBE complexities, energy limitations, and the impact of ion species variations in radiation biology. Addressing questions in particle therapy and space radiation for long-term cell survival. Research at top institutions and potential solutions for improved outcomes.

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Advancements in Particle Therapy Radiation Biology: Challenges and Prospects for Space and Cancer Research

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  1. Bleddyn Jones University of Oxford Gray Institute for Radiation Oncology & Biology 21 Century School Particle Therapy Cancer Research Institute, Oxford Physics. Some remaining questionsin particle therapy radiation biology

  2. Space flights and High LET radiation therapy ! Prospects for long term survival of humans/cells in space will depend on improved knowledge of low and high LET radiation effects and their reduction. Cell experiment range In vitro survival limit Modelling range ? Human total body lethal threshold

  3. Density of ionisation (LET)

  4. RBE - Relative biological effect • Ratio of dose in low/high LET radiation for same bio-effect • Is determined by a multitude of factors: • varies with doseper fractional exposure • linked to cell cycle proliferation and DNA damage repair capacity • varies with LET…..and oxygen tension

  5. Carbon Ion Beam Profile 20-30 times effect in peak c.f. plateau Bragg peak RBE 5-7 Peak is spread or scanned & so RBE is ‘diluted’ i.e. takes on intermediate values and varies with position in a patient. Plateau RBE 1.1

  6. Radiobiological complexity of ions SOBP T. Kanai et al, Rad Res, 147:78-85, 1997 (HIMAC, NIRS, Chiba, Japan)

  7. What can be done at: • Surrey Univ.…vertical nano/micro-ion beam [protons to C ions] • Oxford Univ…..horizontal electrons, vertical -particles, x-rays. • Birmingham Univ….horizontal neutrons • Clatterbridge (NHS) horizontal protons Energy limitations on all beams…only cellular exposures feasible

  8. Obtaining a Biological Effective Dose for high LET radiations • Note : • the low LET / ratio is used • RBEs act as multipliers • RBE values will be between RBEmax and RBEmin depending on the precise dose per fraction • KH is daily high LET dose required to compensate for repopulation KL/RBEmax low doses

  9. Differences between ion species [changes in mass & energy from protons to carbon] with respect to • LET & RBE relationship • LET & OER relationship • Changes in above with cell proliferation, repair, genetics

  10. RBE depends on A and Z ~1 MeV/u ~15 MeV/u • RBE maximum is shifted to higher LET for heavier particles • The shift corresponds to a shift to higher energies

  11. Variation of RBE within patient • LET (and so RBE) will vary with position & mix of Bragg peaks with entrance regions of beams • Adequate model of relationship between LET and LQ parameters  and  is required. • Initial slope d/dLET, position of turnover point and ceiling of effect

  12. Linkage of RBE with known LQ & cell kinetic parameters • Linkage of / ratio with RBEmax. • Prediction of change in RBE with cell proliferation rates, especially as / ratio is itself related to proliferation. • Linkage of RBE with Oxygen Enhancement Ratio [OER] • Explaining above through key gene/biological attributes

  13. Poisson Model of LET and RBE[P[1  event ] = f (, k.LET Exp[-k.LET]) . where initial slope is k . turnover point position is 1/k where dP[1]/dLET=0 . Oxygen dependency also determined by kRBE = H/ L and likewise for 

  14. LET and OER……Hypothesis I

  15. LET and OER……Hypothesis II

  16. RBE and OER for Protons…the old Berkeley data

  17. In vitro, Clatterbridge Hammersmith Theoretical

  18. Batterman 1981 – human lung metastases given neutron exposures Method : use relationship between cell doubling time and / and between / and RBE

  19. S is degree of radiobiological sparing achieved ; S=g[particles]/g[x-rays] × RBE[NT]/RBE[cancer]

  20. What should be the minimum treatment time ? Random sampling of 250 different blood vessels with sinusoidal blood flows with different phases and amplitudes

  21. UK ModellingCarbon ions for early lung cancer (Japan): using Monte Carlo computer simulation of hypoxic and oxic (repopulating) with re-oxygenation flux, reduced oxygen dependency of ion cell kill with typical RBE [see Dale and Jones, Radiobiological Modelling in radiation Oncology] Model accounts for single fraction disrepancy in Japanese clinical results

  22. Could very high radiation dose rate deplete local oxygen ??? X=0.006 Gy-1 100 -700 Gy/hr For 10% hypoxic cells

  23. Malignant Induction Probabilities with compensation for fractionation and high LET Let x be proportion of chromosome breaks  cell kill, and (1-x)  cancer Jones B – J Radiat Protection 2009

  24. Summary: a large research portfolio • Accurate prediction of RBE in different tissues and tumours [DNA damage repair proficiency, repopulation rate]. • Oxygen independence ……quantification and selection • Malignant induction probabilities • How best to place fields given above • Optimum fractionation, dose rate • Optimum cost benefit

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