recent developments and applications of the local effect...
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Recent Developments and Applications of the Local Effect Model (LEM)
23.5.2011 Erice Workshop Hadrontherapy: LEM
M. ScholzGSI Darmstadt
Requirements for Treatment Planning
Challenge: Homogenous distribution of effective dose in treatment volume
Effective dose distribution in normal tissues
RBEDD PhysRBE ⋅=
23.5.2011 Erice Workshop Hadrontherapy: LEM
RBE depends on several factors:• Particle species / LET• Dose• Cell / Tissue type• Oxygen status• ...
Treatment planning for carbon ions
Complex RBE dependencies: E, LET, D, cell type,…
Interpolation/extrapolation required fortreatment planning in HI therapy
23.5.2011 Erice Workshop Hadrontherapy: LEM
treatment planning in HI therapy
HIMACExperimental Data
+ Clinical Neutron Experienceand/or MKM-Model???
GSI / HITBiophysical Modelling
(Local Effect Model LEM)
GSI Approach: Basics of Modelling
Lo
cal D
ose
[Gy]
Photons
Tracks
CellCell nucleus
23.5.2011 Erice Workshop Hadrontherapy: LEM
Carbon ions
Lo
cal D
ose
[Gy]
Photons
Carbon ions, local
Lo
cal D
ose
[Gy]
x10000
GSI Approach: Local Effect Model LEM
Basic Assumption:Increased effectiveness of particle radiation
can be described by a combination of thephoton dose response and microscopic dose distribution
Local Effect (Photons) = Local Effect (Ions)
23.5.2011 Erice Workshop Hadrontherapy: LEM
Local Effect (Photons) = Local Effect (Ions)
+ RBE !
LEM: Transfer of low-LET experience to high-LET
Treatment Planning: GSI approach
in-vitro-Exp.Ions
in-vivo-Exp.Ions
LEM-Model
Biological Characteristics of Cells ααααPhoton, ββββPhoton,Dt
Physical. Characteristics of IonsTrack structure
Feedback fromExperiments
Evolution of LEM:LEM I: 1997
23.5.2011 Erice Workshop Hadrontherapy: LEM
Treatment Planning
LEM I: 1997LEM II: 2007LEM III: 2008LEM IV: 2010
LEM II: SSB + SSB -> DSB
LEM III: Improved Track Structure
LEM IV: Effect derived from DSB distributionDSB + DSB -> complex DSB
Focus on C
Focus on p…O
Basic Idea of LEMIV
Inactivation is a consequence of induction of ‚lethal events‘:
• LEM I-III: Empirical derivation of ‚lethal events‘ • LEM IV: Mechanistic interpretation of ‚lethal events‘
23.5.2011 Erice Workshop Hadrontherapy: LEM
Background: ‚Giant Loop Model‘ of chromatin organization
Johnston et al., Rad.Res. 1998
Yokota et al. JCB 1995
Isolated DSB
clustered DSB
Pattern of DSB distribution after ion irradiation in 2D
Idea of LEMIV-concept
Pattern of DSB distribution after X-irradiation in 2D
23.5.2011 Erice Workshop Hadrontherapy: LEM
nDSB=0
nDSB=1: isolated DSB
nDSB≥2: clustered DSB
DSB distribution in single track can be interpreted as cut-out of X-ray distribution!
• Physics: - Radial Dose Distribution:
• Biology:
Input Parameters
= =
7.1ERTrack∝2
1)(
rrD ∝
23.5.2011 Erice Workshop Hadrontherapy: LEM
- Photon SSB+DSB yield
- Photon Dose Response Curve:Linear shape for D>Dt
- Target Size (Nuclear Size): experimental Data
DYN SSBSSB = DYN DSBDSB =
2)(ln DDDS βα +=−
)()(ln)(ln max tt DDsDSDS −+−=−
Comparison of different LEM versions
HSG cell survival
LEM IILEM IIILEM IVLEM IILEM IIILEM IV
23.5.2011 Erice Workshop Hadrontherapy: LEM
Exp. Data: Furusawa et al., Rad. Res. 2000LEM II: Elsässer et al., Rad. Res. 2007LEM III: Elsässer et al., IJROBP 2008LEM IV: Elsässer et al., IJROBP 2010
Sensitivity AnalysisR
BE
10
RB
E10
RB
E10
RB
E10
Impact of ±25% variation of input parameter X
αααα Dt
23.5.2011 Erice Workshop Hadrontherapy: LEM
LET [keV/µm] LET [keV/µm] LET [keV/µm] LET [keV/µm]
RB
E10
RB
E10
RB
E10
RB
E10
ββββ RN
T.Friedrich, manuscript in preparation
Comparison of LEM with experimental data in-vitro:
First radiobiology experiments performed at HIT:Direct comparison of protons and carbon ions
23.5.2011 Erice Workshop Hadrontherapy: LEM
(Elsässer et al, IJROBP 2010)
LEM IVLEM IVCHO-Cells
Full Simulation of Survival Curves
Typical application of LEM:Approximation of β-term from
the effects of single tracks( → computational speed!)
23.5.2011 Erice Workshop Hadrontherapy: LEM
iDSB
intra-track cDSB
inter-track cDSB
Friedrich et al., submitted to IJRB 2011
β-Term!
Check accuracy:Monte-Carlo simulation
of spatial DSB-distributionfor arbitrarily high fluences
Full Simulation vs. Approximation
Carbon Protons
23.5.2011 Erice Workshop Hadrontherapy: LEM
U. Scholz, work in progress
Clinically relevant range Jones, Br. J. Radiol 2009: βN=1.8*βX for neutrons!
Impact of full simulation on SOBP-calculations
23.5.2011 Erice Workshop Hadrontherapy: LEM
with β-approximation
Carbon, Model with full β-simulation
RBE vs. Dose: Hypofractionation
23.5.2011 Erice Workshop Hadrontherapy: LEM
Calculation based on correlation α/β~Dt (Astrahan, Med. Phys. 2008)
U. Scholz,Work in progress
Comparison with Clinical Data
Temporal Lobe Side Effects
23.5.2011 Erice Workshop Hadrontherapy: LEM
Carbon: Schlampp et al., IJROBP 2010Protons: Pehlivan et al., accepted for IJROBP 2011
Calculated Using LEM
(no signif. diff.LEMI – LEMIV)
Application to Cell transformation: Basics
Competition between induction and killing:
)exp1(exp )()( 22 DDDD TTSSP γγγγ βαβαγ
++− −⋅= Photons
23.5.2011 Erice Workshop Hadrontherapy: LEM
Survival Induction
Particles)exp1(exp )()( 22 DDDDn
TPTPSPSPP βαβα ++− −⋅=
LEM LEM
Application to cell transformation: examples
Direct check for charged particle irradiation:
p … F, 0.5….6 MeV/u
Miller et al. (Radiat. Res. 1995)
C …U, 100…950 MeV/u
Yang et al. (Radiat. Res. 1985)
23.5.2011 Erice Workshop Hadrontherapy: LEM
T. Friedrich et al., unpublished
Application of LEM to neutron radiation
– Determine secondary charged particle recoil spectrum (PHITS)– Apply LEM as for any other mixed particle radiation field– At present: secondary particle spectra for monoenergetic neutrons– Weighted summation for broad neutron energy spectra
50%
23.5.2011 Erice Workshop Hadrontherapy: LEM
G. Iancu et al., unpublished
50%
10%
1%
Application to Cancer Induction:
Induction of lung tumors in mice (Coggle et al. 1988)
200 kV X-raysFemale Male
23.5.2011 Erice Workshop Hadrontherapy: LEM
d[20]Be-NeutronsEn≈7.5 MeV
LEM, En=10 MeVLEM, En=5 MeV
LEM, En=10 MeVLEM, En=5 MeV
(LEM calculations: G. Iancu, T. Friedrich, unpublished)
Comparison with Microdosimetric-Kinetic-Model
• MKM: Two types of lesions in domains with µm size– LI: lethal, unrepairable– LII: sublethal, repair / conversion to lethal lesions (4 rate const.)
• Yield of LI and LII only depends on specific energy deposition z1Din domain per particle traversal
23.5.2011 Erice Workshop Hadrontherapy: LEM
in domain per particle traversal
• Survival is described by:
210 )(ln DDzS D ⋅+⋅+=− ββα
Photon Parameters
Ion Tracks
Application of MKM to carbon ions
HSG-Cells
MKMAv. Exp. Data
23.5.2011 Erice Workshop Hadrontherapy: LEM
Inaniwa et al., PMB 2010
Av. Exp. Data
Conceptual Differences
MKM LEM
LI,LII ~ z1D YDSB ~ ηE,LET z1D
β→0 for high LET
23.5.2011 Erice Workshop Hadrontherapy: LEM
βI= βγ =const.βI→0 for high LETβI>βγ for protons
Single domain statistics Sum of all domains in nucleus
γαα =∞→ I
LETlim γαα <<
∞→ ILETlim
Experimentally testable!
Summary & Conclusion
• LEM IV shows improved accuracy in the therapeutically relevant LET region as compared to previous versions
• Full simulation allows to check accuracy of approximations used in treatment planning
• Full simulation predicts βI>βγ, consistent with experimental results
23.5.2011 Erice Workshop Hadrontherapy: LEM
• Full simulation predicts βI>βγ, consistent with experimental results
• LEM is applicable to predict cell transformation in-vitro and secondary cancer induction in-vivo
• LEM is applicable to neutron radiation based on the knowledge of the secondary charged particle spectrum
• Comparison of models should include conceptual aspects as well as application to large data base of experimental data
Thank you!
• Thilo Elsässer • Thomas Friedrich• Lisa Herr• Gheorghe Iancu• Rebecca Grün
Financial Support:
23.5.2011 Erice Workshop Hadrontherapy: LEM
• Rebecca Grün• Uwe Scholz• Adrian Seeger• Olaf Steinsträter
• Marco Durante• …and the Biophysics Group
EU-FP7-ALLEGRO