Recent Developments and Applications of the Local Effect ...erice2011.na.infn.it/TalkContributions/Scholz_23.pdf · Recent Developments and Applications of the Local Effect Model

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 ⋅=


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


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


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)


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


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‘


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


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 ∝


- 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


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


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


(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!)


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


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


with β-approximation

Carbon, Model with full β-simulation

RBE vs. Dose: Hypofractionation


Calculation based on correlation α/β~Dt (Astrahan, Med. Phys. 2008)

U. Scholz,Work in progress

Comparison with Clinical Data

Temporal Lobe Side Effects


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


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)


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%


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


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


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


Inaniwa et al., PMB 2010

Av. Exp. Data

Conceptual Differences

MKM LEM

LI,LII ~ z1D YDSB ~ ηE,LET z1D

β→0 for high LET


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


• 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:


• Rebecca Grün• Uwe Scholz• Adrian Seeger• Olaf Steinsträter

• Marco Durante• …and the Biophysics Group

EU-FP7-ALLEGRO

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Recent Developments and Applications of the Local Effect ...erice2011.na.infn.it/TalkContributions/Scholz_23.pdf · Recent Developments and Applications of the Local Effect Model