MAGNETIC FIELD EFFECTS ON THE NANOSCOPIC CLUSTER-SIZE DISTRIBUTION FOR THERAPEUTIC PROTON BEAMS

Transcription

1 MAGNETIC FIELD EFFECTS ON THE NANOSCOPIC CLUSTER-SIZE DISTRIBUTION FOR THERAPEUTIC PROTON BEAMS Danielle Tyrrell 1, Dr Susanna Guatelli 2, Prof. Anatoly Rozenfeld 3 1 SZROS, Mater Centre South Brisbane, Danielle_tyrrell@health.qld.gov.au 2 Centre for Medical Radiation Physics, University of Wollongong 3 Centre for Medical Radiation Physics, University of Wollongong

2 Presentation Outline Introduction Project Overview Experimental Evidence Geant4 for nanodosimetry Simulation description Results Conclusion

3 Introduction Absorbed dose (D) is a macroscopic quantity describing energy deposited by radiation in a volume of given mass The efficiency of different types of radiation at causing biological effects results solely from different dose deposition patterns An understanding of the stochastics of energy deposition can give better insight to the biological consequences of the radiation and can be an invaluable for radiological protection purposes, medical applications etc. Nanodosimetry studies energy deposition within nanometric volumes which can be used to predict biological effects

4 Introduction Advances in Image guided radiotherapy techniques have lead to the introduction of MRI linacs for photon and proton radiotherapy. Magnetic field (MF) interacts with moving charged particles which are produced by all types of radiation Understanding the radiobiological consequences of associated with a Magnetic Field on a sub-cellular level is important Magnetic field affects (Raaijmakers et al 2007, Raaymakers et al 2008, Li et al 2001) Build-up dose Penumbral shape Exit dose Effects of a MF on macroscopic proton dose has been investigated with little effect seen due to secondary electrons having lower energy and shorter range than in photon irradiation

5 Project Overview What is the effect of a magnetic field on charged particle tracks? Can a magnetic field change the spatial deposition of dose on a DNA level and alter biological outcomes? Geant4 Monte Carlo was used to study distribution of proton induced charged particle tracks in a DNA molecule Investigated the nanoscopic energy deposition characteristics for protons, energies relevant at the distal end of the bragg peak. Investigated the influence of a magnetic field on secondary electron tracks on a DNA level Use nanoscopic quantities, specifically ionisation cluster-size, to relate charged particle track structure to biological outcomes

6 Experimental Evidence MC studies have shown that high strength magnetic fields affect the spatial distribution of low energy secondary electrons, energies down to 1keV (Nettelbeck et al 2008) In vitro studies have indicated that a magnetic field can decrease cell survival during kv photon irradiation Proton interactions in water produce an abundance of δ-electrons δ-electron average energies <2keV, δ-electron ranges <10nm, any changes to track structure on DNA level may not be evident macroscopically

7 Nanodosimetry It is well established that biological effect is related to spatial deposition of dose and that when multiple ionisations occur in close proximity on a DNA scale, the chance of biological damage for an absorbed dose is increased Nanodosimetry provides a means for determining the distribution of ionisations on a DNA level Experimental dosimetry with nanometric spatial resolution is difficult Monte Carlo simulations can be used to predict nanoscopic tracks play a fundamental role in nanodosimetry MC simulations can be used to characterise the radiation field in terms of energy distributions on nanoscopic level

8 Geant4 for nanodosimetry Geant4 Version ref 04 Geant4-DNA Very low energy extension, designed for microdosimetry applications Extension of physics processes in liquid water down to ev Detailed modelling of track structure to nanometric scale Explicitly simulate all interactions (step-by-step) to precisely reconstruct track structures of ionising particles at nanometre cell and DNA level

9 Geant4-DNA physics processes DNA Physics processes include; Elastic scattering Excitation Ionisation Charge Change Electrons 8.23 ev 1 MeV, (0.025 ev latest release) Protons energies 10 ev 100 MeV (excitation), 100 ev 100 MeV (ionisation) Experimental cross-section data in liquid water is difficult to obtain and not readily available in literature Physics models based on experimental gas-phase data with approximations and semi-empirical corrections based on dielectric formalism to extend the data to the sub kev range

10 Validation of Physics Processes GEANT4-DNA processes model interactions in liquid water however there is a lack of experimental data measured in liquid water Physics evaluated by comparison with experimental data in the gas-phase Qualitative comparisons have found GEANT4-DNA models plausible (Incerti et al 2010) Additional validation performed by comparison with an alternative Monte Carlo codes developed for similar nanoscopic applications (TRIOL, PTB) (Francis et al 2010, Bug et al 2010). Found reasonable agreement with G4-DNA and other MC codes. Measurements in liquid water are needed for full quantitative analysis of GEANT4- DNA models

11 Simulation- Primary Particle Mono-energetic proton pencil beam Resultant δ-electrons have ranges in the order of nm Proton RBE is maximum for energies <10MeV Energies simulated: 1 kev 9 MeV These energies are present in the distal end of the Bragg peak for clinical proton beams

12 Simulation - The Target DNA is the critical the target for radiobiological effects Ionisation clustering is considered a critical property of radiation when predominantly confined to ~10 base pairs 6 nm The DNA target was modelled as a DNA segment consisting of ~ 10 bp. Represented by a water cylinder, 2.3 nm diameter, 3.4 nm height. The nucleosome was modelled surrounding the DNA segment Sensitive volume surrounded by cubic water volume, 150 nm side length 3.4 nm 2.3 nm DNA 10 nm Geometry suitable for correlating results with radiobiological effects on a DNA level (Grosswendt 2002, Nikjoo et al 1997) Nucleosome

13 Simulation Design Protons incident on the surface of the DNA segment A uniform transverse magnetic field was applied along the y-axis B Input parameters: Magnetic field strength: 0-10 Tesla. Proton particle energy: 1keV-9MeV 10 6 incident protons were tracked per simulation p All secondary electrons are transported down to 8.23eV DNA Simulation records/event: Ionisations and excitations z energy deposited position of interaction ROOT analysis used to extract histogram data and determine the cluster-size and mean energy deposited per primary event y x Nucleosome

14 Visualisation 10 kev Proton 80 kev Proton

15 Computational requirements Simulations were run through collaboration with the Queensland University of Technology (QUT) Remote access to the University High Performance Computer, SGI XE Cluster Open source Linux distribution SUSE 404 x 64 bit Intel Xeon processor cores GHz CPU 940 GB of RAM (total)

16 Analysis- Ionisation cluster-size Simulation determined # of ionisations/event (in target) defined as Ionisation cluster-size, v Ionisation cluster-size nanoscopic quantity dependent on track structure, used to relate track structure to initial DNA Damage (Grosswendt et al 2004) Data is used to create a probability distribution, of ionisation cluster-size for each beam quality. The probability distribution describes the probability P v (Q), that an exact number, of ionisations, v, is produced by a primary particle of radiation quality, Q. The mean of the probability distribution, M 1 (Q), was used is used to characterise the radiation quality in terms of its track structure The mean cluster-size was determined for each beam quality and used to evaluate any changes in the secondary electron distribution with a MF

17 Results Mean energy deposited in sensitive volume Mean energy/primary particle deposited by all primary and secondary particles in DNA Maximum for 80 kev protons Minimum for E>2MeV Mean Energy Deposited, ev Initial Proton Energy, kev DNA Segment

18 DNA Results Ionisation cluster-size probability distribution, P v (Q) # of ionisations per primary particle was scored in DNA, used to create a probability distribution for each energy 1.0E E-01 (a) 50 and 80 kev protons are more likely to form larger clusters in DNA than other energies. Pv(Q) 1.0E E-03 10keV 20keV 50keV 80keV Clusters of 5-8 ionisations are most probable for 50 and 80 kev protons 1.0E Ionisation cluster size, v (b) 1.0E+00 Clusters of 3-6 ionisations are required for a DSB(Goodhead 1989, 1994, Brenner and Ward 1992 ) Pν(Q) 1.0E E-02 80keV 200keV 400keV 800 kev 1.0E-03 Protons of 50 and 80 kev are highly efficient at causing biologically relevant DNA damage 1.0E Ionisation cluster size, v

19 Results Mean ionisation cluster-size M 1 (Q) Mean ionisation cluster-size was used to characterise the probability distribution The mean cluster-size was used to represent the efficiency of each proton energy at causing DNA damage The largest mean cluster-size occurs for energies kev Mean cluster size, M1(Q) DNA Nucleosome Proton Energy (kev)

20 Results Magnetic Field Effect on mean energy deposition Mean energy deposited in DNA remains unchanged under the influence of the MF (1-10T) Mean Energy Deposited/event, ev Mean Energy Deposited/event, ev Tesla MF Mean energy deposited in in DNA segment Incident Proton Energy, kev No MF No MF 3 Tesla MF 3 Tesla MF

21 Results Magnetic Field Effect on M 1 (Q) Mean Ionization Cluster-size appears to be unaffected by MF strength 6 Mean Ionisation cluster-size in DNA, M 1 (Q) Mean Cluster-size/event Mean Cluster-size/event 5 Mean Ionisation cluster-size in DNA, M 1 (Q) No MF 6 3 Tesla MF 4 5 No MF Tesla MF Initial 100 Proton Energy, kev 1000 Initial Proton Energy, kev 10000

22 Results Magnetic Field Effect on M 1 (Q) For 100 kev protons- high probability of producing larger cluster-sizes, no significant difference in seen in mean ionization cluster-size with MF Data is normalized to that with no MF Error bars represent the standard deviation of the mean, 95 % confidence level 100 kev protons 1.04 DNA segment M 1 (B)/M 1 (0) Magnetic Field Strength, B(T)

23 Results Magnetic Field Effect on M 1 (Q) For energies with high probability of forming small clusters in DNA, no significant change in mean cluster-size was seen with MF Statistic analysis (Kolmogorov-Smirnov test) found no differences in the mean ionization cluster-size distributions for all strength MF tested 20 kev protons M 1 (B)/M 1 (0) DNA segment Magnetic Field Strength, B(T)

24 Results Summary Protons in the energy range of keV showed maximum biological effectiveness based on energy deposition in nanometric targets The mean cluster-size in a MF did not vary by more than 5% from that with no MF. All deviations were within the standard error and not considered significant Results show no significant change in energy deposition or mean ionisation cluster-sizes in DNA or Nucleosome volumes with MF strength up to 10T

25 Conclusion Geant4-DNA MC can be used to determine spatial distribution of dose in nanometric targets Geant4 can be used for investigation into change in Proton RBE with energy by studying energy deposition in nanometric volumes further research required to relate cluster-size in DNA to cellular dose-response effects MC results found no evidence that transverse magnetic fields in proton irradiation cause spatial redistribution of δ-electron tracks as measurable by a change in ionisation cluster size. Simulations only accounted for interactions of δ-electron, and not those of free radicals generated around the DNA (species are created but not tracked)

26 Future work Further investigation into magnetic field effects to find conclusive evidence of the mechanisms of biological enhancement in a magnetic field Use of simulation codes devoted to the study of the physical and chemical processes of radical species generated the DNA environment Futher experiments in condensed phase water is required for full validation of the G4-DNA physics models Future experimental measurements of cell survival in proton irradiation when exposed to a magnetic field should be conducted Current measurements are being performed at the PTB Institute in Germany.

27 Magnetic Field Effects References Raaijmakers, AEJ, Raaymakers, BW, Lagendijk, JJW. Experimental verification of magnetic field dose effects for the MRIaccelerator. Phys. Med. Biol 2007; 52:4283 Raaymakers, BW, Raaijmakers, AJE, Lagendijk, JJW. Feasibility of MRI guided proton therapy: magnetic filed dose effects. Phys. Med. Biol 2008;53: Li, XA, Reiffel, L, Chu, J, Naqvi, S. Conformal photon-beam therapy with transverse magnetic fields: A Monte Carlo study. Medical Physics 2001;28: Geant4 Models and Validation Chauvie, S, Incerti, B, Moretto, Pia, MG. Evaluation of Phase Effects in Geant4 Microdosimetry Models for Particle Interactions in Water. IEEE Transactions on Nuclear Science Symposium Conference Record 2007: Francis, Z, Incerti, B, Capra, R, et al. Molecular scale track structure simulations in liquid water using the Geant4-DNA Monte-Carlo processes. Applied Radiation and Isotopes Incerti, S, Ivanchenko, A, Karamitros, M, et al. Comparison of GEANT4 very low energy cross section models with experimental data in water. Medical Physics 2010;37: Baek, WY, Grosswendt, B, Willems, G. Ionization ranges of protons in water vapour in the energy range kev. Radiat Prot Dosimetry 2006;122: Spiga, J, Siegbahn, EA, Brauer-Krisch, E, Randaccio, P, Bravin, A. Microdosimetry for Microbeam Radiation Therapy (MRT): theoretical calculations using the Monte Carlo toolkit. Nuclear Science Symposium Conference Record, IEEE. 2006; Chauvie, S, Francis, Z, Guatelli, S, et al. Monte Carlo Simulation of Electromagnetic Interactions of Radiation with Liquid Water in the Framework of the Geant4-DNA Project. Nuclear Science Symposium Conference Record, IEEE. 2006; Chauvie, S, Francis, Z, Guatelli, S, et al. Geant4 Physics Processes for Microdosimetry Simulation: Design Foundation and Implementation of the First Set of Models. IEEE Transactions on Nuclear Science 2007;54: Bug M U, Gargioni E, Guatelli S, Incerti S, Rabus H, Schulte R and Rosenfeld A B 2010 Effect of a magnetic field on the track structure of low-energy electrons: a Monte Carlo study Eur. Phys. J. D

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