enlight meeting local effect model – status and …...enlight meeting local effect model –...
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Valencia, 18.06.09
ENLIGHT Meeting
Local Effect Model –
Status and future perspectives
Thilo Elsässer
GSI Darmstadt
Valencia, 18.06.09
Menu
- Motivation
- Relative Biological Effectiveness (RBE)
- Local Effect Model (LEM)
- Application in-vitro and in-vivo
- Clinical application – biological treatment planning
- Prospectives
Valencia, 18.06.09
Higher biological effectiveness
Nanometer scale
complex damage due to localized energy deposition
©NASA
low energy
M.Krämer
Nanometer scale
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Relative Biological Effectiveness (RBE)S
urvi
val
Dos
e [G
y]
Penetration Depth [mm]
Carbon 195 MeV/u
IsoeffectIonD
DRBE γ=
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Systematic of RBE: Survival curves
• Increasing effectiveness with decreasing energy• Saturation effects at very low energies (<10 MeV/u)• Transition from shouldered to straight survival curves
Weyrather et al.IJRB 1999
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RBE depends on LET
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RBE changes with Depth
Extended Bragg peak / SOBP irradiation:Distal part: mainly Bragg peak ions => high RBE
Proximal part: mix of Bragg peak and higher energies => moderate RBE
Carbon ion irradiation
Weyrather et al.
peak dosepeak dosepeak dose
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RBE depends on Ion Species
• 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
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RBE depends on Cell / Tissue Type
• Cells with higher repair capacity show higher RBE
CHO (normal repair) XRS-5 (repair deficient)
Weyrather et al., IJRB 1999
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Challenge
Challenge: Homogeneous distribution of effective dose in target volume
RBEDD Physeff ⋅=
RBE depends on several factors:• Particle species• Energy/ LET• Cell / Tissue type• Dose• ... 0
2
4
6
8
10
Physical dose
12C0
2
4
6
8
10
Dos
e [G
y]
Biol. effective dose
12
0
2
4
6
8
10
Physical dose
12C0
2
4
6
8
10
Dos
e [G
y]
Biol. effective dose
12
Modelling is required
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Main assumption of LEM
Same average dose - different local distribution
Biological damage is determined by local dose
No qualitative difference since damage is generated by ejected δ-electrons
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Repair Processes
Transition G1 S-Phase Transition G2 M-Phase
Too complicated for Physicists, Doctors and even Biologists !!!
incredibly high number of degrees of freedom
large uncertainties and too little knowledge
Too complicated for Physicists, Doctors and even Biologists !!!
incredibly high number of degrees of freedom
large uncertainties and too little knowledge
Valencia, 18.06.09
Local Effect Model (LEM)
tDD DDeS <= +− ,)( 2βα
2
1)(r
rD ∝
PhysicsRadial Dose Distribution:Monte-Carlo (Krämer), Experimental Data
GeometryTarget (cell nucleus): Experimental Data
BiologyPhoton Response Curve:additional assumptionsfor large doses
Dt
tDDs DDeS t ≥= −− ,)(maxη
Local Effect (Ions) =Local Effect (Photons)
Scholz et al., Rad. Environ. Biophys. 1997
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Simulation according to LEM
Dose
nucleus
"Lethal Event Density"0 2 4 6 8 10
4
3
2
1
0
0,01
0,1
1
# le
thal
eve
nts
Dosis (Gy)
Sur
viva
l
X-ray
Integration of all pixels -> survival after ion irradiation
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Radial Dose Distribution
Physical Dose Distribution Radical Diffusion (LEM II)
∫ ∫∞
′′−′′′′=0
2
0
),()()(~ π
φφ rrfrDdrrdrD
1E-4 1E-3 0,01 0,1 1100
101
102
103
104
105
rmax
Dos
e (G
y)
Radius (µm)
rmin
1/r2
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High Dose Cluster Effects (LEM II)
Double StrandBreak
Single StrandBreak
Single StrandBreak
< 25bp
Experiments with plasmids
• Non-linear yield of DSB• Clustered SSBs reason for non-linearity• Stagger size between 5 bp and 60 bp
Elsässer and Scholz Rad.Res. 2007
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Energy dependent track center (LEM III)
1 10 1000
10
20
30
r min
(nm
)
E(MeV/u)
track center extension dependson particle energy(adiabaticity principle)
=>
rmin=40nm·β β=v/c
40nm - empirically adjustedfor bestagreement with ion data 1E-4 1E-3 0,01 0,1 1
100
101
102
103
104
105
rmax
Dos
e (G
y)
Radius (µm)
rmin
1/r2
Elsässer et al., Int.J.Radiat Oncol Biol Phys 2008Elsässer et al., New Journal of Physics 2008
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Dose dependence
Combs et al., IJRB (2009)
Example: Glioblastoma cell lines irradiated by carbon ions
center SOBP center SOBP
distal part SOBP
distal part SOBP
comparison with LEM II
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Comparison for different cell lines
Elsässer and Scholz, AIP conference proceedings (2009)
LEM III
carbon irradiation
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Accuracy of LEM
Plateau (13 keV/µm)
distal SOBP(77 keV/µm)
Different human cell lines of tumor and normal tissue
Exp. Data: Suzuki et al., IJROBP 2000
RBE(α/β low)>RBE(α/β high)
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Estimation clinical / in-vivo RBE
Knowledge: βγ/αγ-ratio for clinical / in-vivo endpoint
αβαβ //vitroinvivoin RBERBE −− =
Assumption: Correlation βγ/αγ − RBE:
clinical / in-vivo RBE
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Radiation tolerance – rat spinal cord
Experimental dataKarger et al. 2006
Tolerance of normal tissue (nerves)
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Treatment Planning
LEM-Model
Biol. Char. Photons
Phys. Char.Ions
Input
in-vitro-Exp.Ions
in-vivo-Exp.Ions
Verification
Treatmentplanning
Integration
Evolution of LEM:LEM I: 1997LEM II: 2007LEM III: 2008ULEM: 2009
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RBE-Map
Krämer et al.
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Current research topics
• Thorough analysis of uncertainties
• Biological dose of neutrons in carbon ion therapy –ALLEGRO
• ROCOCO – comprehensive comparison of different treatment modalities
• Improvement and validation of input data for LEM (e.g. trackstructure)
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Future Perspective
• Clinical validation of new model versions• Clinical validation of new tumor entities• Comparison to Japanese clinical data• Second cancer risk• Hypoxia• Hypofractionation• Preparation for new particles (e.g. helium)
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Summary
Surv
ival
Treatment Planning, Track Structure
Michael Krämer
Biophysical Modeling
Michael Scholz, Thomas Friedrich, Gheorghe Iancu, Rebecca Grün
Cell survival studies
Wilma Kraft-Weyrather
Head of the Group
Marco Durante(Gerhard Kraft)