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

Valencia, 18.06.09

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

Valencia, 18.06.09

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

Valencia, 18.06.09

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

Valencia, 18.06.09

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)

Valencia, 18.06.09

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)