![Page 1: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/1.jpg)
The Increased Biological Effectivenessof Heavy Charged Particle Radiation:
From Cell Culture Experiments to Biophysical Modelling
Michael Scholz
GSI Darmstadt
![Page 2: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/2.jpg)
Ion Beams for Tumor Therapy
Advantage of ion beams for therapy:
Physical aspects:• Inverted depth dose profile• Defined penetration depth• Reduced lateral scattering
Biological aspects:• Increased effectiveness• Reduced oxygen effect
![Page 3: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/3.jpg)
Inverted Depth Dose Profile
Bragg Peak
![Page 4: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/4.jpg)
Biological Advantage: Increased Effectiveness
Sur
viva
l
D
ose
[Gy]
Penetration Depth [mm]
Carbon 195 MeV/u
Differential Effect:
RBE(Depth)>
RBE(Entrance)
![Page 5: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/5.jpg)
Cell Survival
t=15minTges=85h
G. Böhrnsen/I. Katayama
V79 Chinese Hamster Cells
Survivor:
1 cell 50 cells(t=0) (t=7d)
„Colony forming“
100m
![Page 6: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/6.jpg)
Survival after Photon Irradiation
1a
1b
1c
1d
1e
1f
t~24h
)( 2DD
seed
col eN
NS
G. Böhrnsen
Shoulder Repair
![Page 7: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/7.jpg)
Survival after Carbon Ion Irradiation
Increasing effectiveness with decreasing energy Saturation effects at very low energies (<10 MeV/u) Transition from shouldered to straight survival curves
W. Kraft-Weyrather
![Page 8: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/8.jpg)
Definition of Relative Biological Effectiveness
IsoeffectIonD
DRBE
![Page 9: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/9.jpg)
RBE depends on LET
W. Kraft-Weyrather
![Page 10: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/10.jpg)
RBE depends on Dose
RBE decreases with dose Dose dependence more pronounced for lower energies
W. Kraft-Weyrather
![Page 11: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/11.jpg)
RBE depends on Cell Type
Resistant cells Sensitive cells
Increase of effectiveness is more pronounced for resistant tumors compared to sensitive tumors
W. Kraft-Weyrather
![Page 12: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/12.jpg)
RBE depends on Cell Type
RBE is higher for resistent (repair proficient) cell types
W. Kraft-Weyrather
![Page 13: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/13.jpg)
RBE depends on 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
W. Weyrather et al.
![Page 14: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/14.jpg)
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
![Page 15: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/15.jpg)
Why Carbon Ions?
Ne 400 MeV/uO 325 MeV/uC 270 MeV/uNe 11 MeV/uO 11 MeV/uC 11 MeV/u
Dose [Gy]
Sur
viva
l
Increase of RBE from entrance channel to Braggpeak region is most pronounced for carbon ions
W. Kraft-Weyrather
![Page 16: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/16.jpg)
Explanation of increased effectiveness
X-rays Carbon
10 m
Cell
nucleus
M. Krämer
![Page 17: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/17.jpg)
Radiation induced DNA damage
Cells are able to repair radiation induced DNA damage
Single StrandBreak
UVionizing
Radiation
Double StrandBreak
Base Modification
Dimer
Base Loss
DNA Double Helix2 nm
3.4
nm
![Page 18: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/18.jpg)
Cellular Repair Pathways
Transition G1 S-Phase Transition G2 M-Phase
![Page 19: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/19.jpg)
Can we model it from first principles?
>100 (free?) parameters!Precision ????
(DNA-Model: Friedland et al.)
Initial damage
...
Processing of damage
G2/M DNA Damage Checkpoint
![Page 20: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/20.jpg)
Radial Dose Profile of Particle Tracks
(M. Krämer)
Radial Dose Profile:D(r): Expectation value
D(r) ~ 1/r2
RTrack ~ Ec
![Page 21: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/21.jpg)
Microscopic Local Dose Distribution
Cell
Nucleus
+
![Page 22: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/22.jpg)
Visualization of Local Biological Effect
CDKN1A/p21: greenDNA: red
Pb-ions, 3.1 MeV/u, 3x106/cm2
B. Jakob et al.
Cell Nucleus
Tracks in CR39
p21 response
Ca-ions, 10.1 MeV/u, 2x106/cm2
M. Scholz et al.
![Page 23: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/23.jpg)
Biological Visualization of Particle Tracks
sample holdersample holder
B. Jakob et al.
![Page 24: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/24.jpg)
Amorphous Track Structure Models
Basic Assumption:Increased effectiveness of particle radiation
can be described by a combination of thephoton dose response and microscopic dose distribution
+ RBE !
![Page 25: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/25.jpg)
Principle of Local Effect Model
Low-LET dose response:
Event density:
2)(ln)( DDDSDN Xlethal
Nucleuslethal VDND /)()(
lethalNeS
Local biological effect:
NucleusNucleus
Xlethal dV
V
zyxdSN
)),,((ln
M. Scholz et al.
![Page 26: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/26.jpg)
Input Parameters
• Radial Dose Distribution:Monte-Carlo (M. Krämer), Analytical Models (Katz, Kiefer), Experimental Data
• X-ray Survival Curves:Experimental data according to LQ; additional assumption: Transition from shoulder to exponential shape at high doses
• Target Size (Nuclear Size):Experimental Data
7.1ERTrack 2
1)(r
rD
tDD DDeS ,)( 2
tDDs DDeS t ,)(max
![Page 27: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/27.jpg)
Algorithms
• Exact calculation:– Monte-Carlo method for determination of ion impact parameters– Numerical integration (taking into account overlapping tracks in
detail)
• Approximation:– Exact calculation of single particle effects (corresponding to initial
slope of survival curve)– Estimation of -term from boundary condition:
Max. slope of HI curve = max. slope of photon dose response curve
![Page 28: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/28.jpg)
Comparison with experimental data
Data: Kraft-Weyrather et al.
Sur
viva
l
![Page 29: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/29.jpg)
Comparison with experimental data
Data: Weyrather et al., IJRB 1999
![Page 30: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/30.jpg)
Dependence on Particle Species
(Including improvement of LEMwith respect to cluster effects)
Influence of track structure; for given LET: E(C)>E(He)>E(p) Rtrack(C)>Rtrack(He)>Rtrack(p)
![Page 31: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/31.jpg)
Application to Tissue Effects
Tissues show complex response to radiation
Correlation with cell survival?
Nerve tissue: non proliferating cells
Clonogenic survival not defined
Which parameters of photon dose response
define RBE?
![Page 32: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/32.jpg)
Correlation Shoulder – RBE: Theory
Calculation of mid peak RBE
Carbon 6-10cm SOBP
Constant XX-ratio
Varying absolut XX values
Constant X-value
Varying XX-ratios
XX-ratio determines RBE
![Page 33: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/33.jpg)
Application to Normal Tissue Effects
Zacharias et al., Acta Oncol. 1997
Skin reaction in minipigs
![Page 34: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/34.jpg)
Role of Modeling for Treatment Planning in Heavy Ion Tumor Therapy
in-vitro-Exp.Ions
in-vivo-Exp.Ions
LEM-Model
Biol. Char. Photons
Phys. Char.Ions
Treatmentplanning
![Page 35: The Increased Biological Effectiveness of Heavy Charged Particle Radiation: From Cell Culture Experiments to Biophysical Modelling Michael Scholz GSI Darmstadt](https://reader033.vdocuments.mx/reader033/viewer/2022051401/56649ea45503460f94ba8ab3/html5/thumbnails/35.jpg)
Summary
• Biological advantage of ion beams in tumor therapy: increased effectiveness in Bragg peak region
• Increased effectiveness depends on factors like dose, ion species & energy, cell type, ...
• Complex dependencies require modeling for treatment planning in ion tumor therapy
• Modeling cannot be based on first principles
• Empirical approaches based on a link to the photon dose response curves allow high quantitative precision