Some remaining questionsSome remaining questionsin particle therapy radiation in particle therapy radiation biologybiology

Bleddyn JonesBleddyn JonesUniversity of OxfordUniversity of Oxford1.1. Gray Institute for Radiation Oncology & BiologyGray Institute for Radiation Oncology & Biology2.2. 21 Century School Particle Therapy Cancer Research 21 Century School Particle Therapy Cancer Research

Institute, Oxford Physics.Institute, Oxford Physics.

Space flights and High Space flights and High LET radiation therapy !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)Density of ionisation (LET)

RBE - Relative RBE - Relative biological effectbiological effect Ratio of dose in low/high LET radiation Ratio of dose in low/high LET radiation

for same bio-effectfor same bio-effect Is determined by a multitude of Is determined by a multitude of

factors:factors:

1.1. varies with varies with dosedose per fractional per fractional exposure exposure

2.2. linked to linked to cell cyclecell cycle proliferation and proliferation and DNA damage repairDNA damage repair capacity capacity

3.3. varies with varies with LETLET…..and …..and oxygen tensionoxygen 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 Radiobiological complexity of ions SOBPSOBP

T. Kanai et al, T. Kanai et al, Rad ResRad Res, 147:78-85, 1997 (HIMAC, NIRS, Chiba, Japan), 147:78-85, 1997 (HIMAC, NIRS, Chiba, Japan)

What can be done at:What can be done at:

Surrey Univ.…vertical nano/micro-ion Surrey Univ.…vertical nano/micro-ion beam [protons to C ions]beam [protons to C ions]

Oxford Univ…..horizontal electrons, Oxford Univ…..horizontal electrons, vertical vertical -particles, x-rays.-particles, x-rays.

Birmingham Univ….horizontal neutronsBirmingham Univ….horizontal neutrons Clatterbridge (NHS) horizontal protonsClatterbridge (NHS) horizontal protons

Energy limitations on all beams…only Energy limitations on all beams…only cellular exposures feasiblecellular exposures feasible

)()/(

minmax

)/(

minmax

.

,

;

)(

2

2

2

2

2

KHL

H

LH

HLMIN

L

HMIN

L

HMAX

L

HH

L

HH

L

HHHH

TTKRBE

RBEndBED

RBERBEndBED

Thence

RBE

RBE

RBE

ddn

EBED

ddNE

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. KH is daily high LET dose required to compensate for repopulation KL/RBEmax low doses

Differences between ion species Differences between ion species [changes in mass & energy from [changes in mass & energy from protons to carbon] with respect protons to carbon] with respect toto

LET & RBE relationshipLET & RBE relationship LET & OER relationshipLET & OER relationship Changes in above with cell Changes in above with cell

proliferation, repair, genetics 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 Variation of RBE within patientpatient LET (and so RBE) will vary with LET (and so RBE) will vary with

position & mix of Bragg peaks position & mix of Bragg peaks with entrance regions of beamswith entrance regions of beams

Adequate model of relationship Adequate model of relationship between LET and LQ parameters between LET and LQ parameters and and is required. is required.

Initial slope dInitial slope d/dLET, position of /dLET, position of turnover point and ceiling of effectturnover point and ceiling of effect

Linkage of RBE with Linkage of RBE with known LQ & cell kinetic known LQ & cell kinetic parametersparameters Linkage of Linkage of // ratio with RBEmax. ratio with RBEmax. Prediction of change in RBE with Prediction of change in RBE with

cell proliferation rates, especially cell proliferation rates, especially as as // ratio is itself related to ratio is itself related to proliferation.proliferation.

Linkage of RBE with Oxygen Linkage of RBE with Oxygen Enhancement Ratio [OER]Enhancement Ratio [OER]

Explaining above through key Explaining above through key gene/biological attributesgene/biological attributes

Poisson Model of LET and RBEPoisson Model of LET and RBE

[P[1 [P[1 event ] = f ( event ] = f (, k.LET Exp[-k.LET]) , k.LET Exp[-k.LET])

. where initial slope is k . where initial slope is k

. turnover point position is 1/k where . turnover point position is 1/k where dP[1]/dLET=0dP[1]/dLET=0

. Oxygen dependency also determined by k . Oxygen dependency also determined by k

RBE = RBE = HH/ / L L and likewise for and likewise for

LET and OER……Hypothesis I

LET and OER……Hypothesis II

RBE and OER for Protons…RBE and OER for Protons…the old Berkeley datathe 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]

dnt

ztum

L

H

ERBE

ERBES

g

g

L

Heq

d

dS

L

Heq

d

dS

L

Heq

d

dS

0 2 4 6 8 1 0 1 2 1 42 3

2 4

2 5

2 6

2 7

T i m e m i n u t e s

Tum

our

Blo

odF

low

What should be the minimum treatment time ?

Random sampling of 250 different blood vessels with sinusoidal blood flows with different phases and amplitudes

20 30 40 50 60 70 80 90TOTAL DOSECo Eq Gy

20

40

60

80

100PERCENTAGE CURES

1# 4# 9# 18#

UK ModellingUK Modelling Carbon ions for early lung cancer (Japan): using Monte Carlo computer Carbon ions for early lung cancer (Japan): using Monte Carlo computer simulation of hypoxic and oxic (repopulating) with re-oxygenation flux, simulation of hypoxic and oxic (repopulating) with re-oxygenation flux, reduced oxygen dependency of ion cell kill with typical RBE [see Dale reduced oxygen dependency of ion cell kill with typical RBE [see Dale and Jones, Radiobiological Modelling in radiation Oncology]and Jones, Radiobiological Modelling in radiation Oncology]

Model accounts for single fraction disrepancy in Japanese clinical results

100 -700 Gy/hr

Could very high radiation dose rate deplete local oxygen ???X=0.006 Gy-1

For 10% hypoxic cells

Malignant Induction Malignant Induction Probabilities with Probabilities with compensation for compensation for fractionation and high LETfractionation and high LET

)(2max

2max).()1( ddRxneddRnxMIP

Let x be proportion of chromosome breaks cell kill, and (1-x) cancer

Jones B – J Radiat Protection 2009

Summary: a large Summary: a large research portfolioresearch portfolio Accurate prediction of RBE in different Accurate prediction of RBE in different

tissues and tumours [DNA damage tissues and tumours [DNA damage repair proficiency, repopulation rate].repair proficiency, repopulation rate].

Oxygen independence ……Oxygen independence ……quantification and selectionquantification and selection

Malignant induction probabilitiesMalignant induction probabilities How best to place fields given aboveHow best to place fields given above Optimum fractionation, dose rateOptimum fractionation, dose rate Optimum cost benefitOptimum cost benefit