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Some remaining questions in particle therapy radiation biology

Bleddyn Jones University of Oxford Gray Institute for Radiation Oncology & Biology 21 Century School Particle Therapy Cancer Research Institute, Oxford Physics. Some remaining questions in particle therapy radiation biology. Space flights and High LET radiation therapy !.

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Some remaining questions in particle therapy radiation biology

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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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