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

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 Modelling range ? In vitro survival limit Human total body lethal threshold

Density of ionisation (LET)

RBE - Relative biological effect Ratio of dose in low/high LET radiation for same bio-effect Ratio of dose in low/high LET radiation for same bio-effect Is determined by a multitude of factors: Is determined by a multitude of factors: 1. varies with dose per fractional exposure 2. linked to cell cycle proliferation and DNA damage repair capacity 3. varies with LET…..and oxygen tension

Carbon Ion Beam Profile Bragg peak RBE 5-7 Plateau RBE 1.1  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] Surrey Univ.…vertical nano/micro-ion beam [protons to C ions] Oxford Univ…..horizontal electrons, vertical  -particles, x-rays. Oxford Univ…..horizontal electrons, vertical  -particles, x-rays. Birmingham Univ….horizontal neutrons Birmingham Univ….horizontal neutrons Clatterbridge (NHS) horizontal protons Clatterbridge (NHS) horizontal protons Energy limitations on all beams…only cellular exposures feasible

Obtaining a Biological Effective Dose for high LET radiations Note : 1.the low LET  /  ratio is used 2.RBEs act as multipliers 3.RBE values will be between RBEmax and RBEmin depending on the precise dose per fraction 4.K H is daily high LET dose required to compensate for repopulation  K L /RBE max low doses

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

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

Variation of RBE within patient LET (and so RBE) will vary with position & mix of Bragg peaks with entrance regions of beams 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. Adequate model of relationship between LET and LQ parameters  and  is required. Initial slope d  /dLET, position of turnover point and ceiling of effect 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. Linkage of  /  ratio with RBEmax. Prediction of change in RBE with cell proliferation rates, especially as  /  ratio is itself related to proliferation. 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] Linkage of RBE with Oxygen Enhancement Ratio [OER] Explaining above through key gene/biological attributes 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 is degree of radiobiological sparing achieved ; S=g[particles]/g[x-rays] × RBE[NT]/RBE[cancer]

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

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] Model accounts for single fraction disrepancy in Japanese clinical results

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

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

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