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