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Some remaining questions in particle therapy radiation biology Bleddyn Jones University of Oxford 1. Gray Institute for Radiation Oncology & Biology 2. 21 Century School Particle Therapy Cancer Research Institute, Oxford Physics. Space flights and High LET radiation therapy ! Cell experiment In vitrorange survival limit Modelling range ? Human total body lethal threshold 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. Density of ionisation (LET) RBE - Relative biological effect 1. 2. 3. Ratio of dose in low/high LET radiation for same bio-effect Is determined by a multitude of factors: varies with dose per fractional exposure linked to cell cycle proliferation and DNA damage repair capacity varies with LET…..and oxygen tension Carbon Ion Beam Profile Bragg peak RBE 5-7 Plateau RBE 1.1 20-30 times effect in peak c.f. plateau Peak is spread or scanned & so RBE is ‘diluted’ i.e. takes on intermediate values and varies with position in a patient. Radiobiological complexity of ions SOBP T. Kanai et al, Rad Res, 147:78-85, 1997 (HIMAC, NIRS, Chiba, Japan) 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 Obtaining a Biological Effective Dose for high LET radiations Note : E N ( H d H H d H ) 2 1. the low LET / ratio is used H dH H dH 2 BED n L L L E RBE MAX RBE MIN 2. RBEs act as multipliers H ; L 3. RBE values will be between RBEmax and RBEmin depending on the precise dose per fraction H , L RBE MIN . L H 2 Thence RBE min BED nd H RBE max ( / ) L 2 RBE min 2 K H (T TK ) BED nd H RBE max ( / ) L 4. KH is daily high LET dose required to compensate for repopulation KL/RBEmax low doses 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 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 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 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 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 k RBE = H/ L and likewise for LET and OER……Hypothesis I LET and OER……Hypothesis II RBE and OER for Protons…the old Berkeley data In vitro, Clatterbridge Hammersmith Theoretical Batterman 1981 – human lung metastases given neutron exposures Method : use relationship between cell doubling time and / and between / and RBE S d Heq dL S is degree of radiobiological sparing achieved ; S=g[particles]/g[x-rays] × RBE[NT]/RBE[cancer] S d Heq dL RBE tum E z gH S gL RBE nt Ed What should be the minimum treatment time ? Random sampling of 250 different blood vessels with sinusoidal blood flows with different phases and amplitudes Tumour Blood Flow 27 26 25 24 23 0 2 4 6 8 10 Time minutes 12 14 UK Modelling Carbon 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] PERCENTAGE CURES 100 Model accounts for single fraction disrepancy in Japanese clinical results 80 60 4# 1# 9# 18# 50 60 40 20 TOTAL DOSE Co Eq Gy 20 30 40 70 80 90 Could very high radiation dose rate deplete local oxygen ??? X=0.006 Gy-1 For 10% hypoxic cells 100 -700 Gy/hr Malignant Induction Probabilities with compensation for fractionation and high LET Let x be proportion of chromosome breaks cell kill, and (1-x) cancer MIP (1 x)n(dRmax d ).e 2 xn (dRmax d 2 ) Jones B – J Radiat Protection 2009 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