the biological rationale of hadron therapy...j.j. wilkens - tum department of radiation oncology the...
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J.J. Wilkens - TUM Department of Radiation Oncology
The biological rationale of hadron therapy
Jan J. Wilkens Department of Radiation Oncology www.radonc.med.tum.de
ICMP 2013
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J.J. Wilkens - TUM Department of Radiation Oncology
Introduction
Recent developments in radiotherapy: biologically adaptive treatment strategies • functional imaging • TCP/NTCP calculations and optimization • … Hadrons (protons, ions, neutrons): „biological effects“ due to changes in radiation quality
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J.J. Wilkens - TUM Department of Radiation Oncology
Bragg peak
rela
tive
dose
(%)
depth (cm)
megavoltage x-rays protons
exponential falloff
SOBP
rela
tive
dose
(%)
depth (cm)
The physical advantage of protons (and ions)
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J.J. Wilkens - TUM Department of Radiation Oncology
Biological effectiveness
low LET high LET biologically more effective
rela
tive
dose
(%)
depth (cm)
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J.J. Wilkens - TUM Department of Radiation Oncology
The relative biological effectiveness (RBE)
The RBE depends on:
• particle type (p, n, 12C, …), LET / local energy spectrum, dose • tissue type, biological endpoint
RBE(proton) ≈ 1.1 RBE(carbon ions, neutrons) ≈ 2 … 5
hadron
photon
DD
RBE =
for the same biological effect
Definition of the RBE:
dose (Gy)
survival photons
hadrons
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J.J. Wilkens - TUM Department of Radiation Oncology
RBE-weighted absorbed dose
“RBE-weighted absorbed dose” = RBE(x,y,z) × dose(x,y,z)
• units: Gy(RBE) [ICRU] (formerly: GyE or CGE)
• hypothetical (!) photon dose distribution with the same biological effect
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J.J. Wilkens - TUM Department of Radiation Oncology
Biological optimization for carbon ions
optimize RBE×dose instead of the dose
Chen et al. 1979 IJROBP 5(10) 1809-19
physically optimized SOBP biologically optimized SOBP
(Gy(
RB
E))
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J.J. Wilkens - TUM Department of Radiation Oncology
Techniques for biological optimization
Two main parts: a) biological model to calculate RBE e.g. “local effect model” LEM (GSI Darmstadt/Germany) b) incorporation of this model into optimization / objective function to optimize RBE×dose in treatment planning Problem: RBE depends nonlinearly on dose
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J.J. Wilkens - TUM Department of Radiation Oncology
Example: carbon ion planning
RBE x dose (100% = 3 Gy(RBE)) dose (100% = 1 Gy)
Single field plan
(RBE for chordoma cells/LEM) Wilkens et al. 2006 Phys
Med Biol 51(12) 3127-40
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J.J. Wilkens - TUM Department of Radiation Oncology
Problems with RBE
• RBE>1 is not necessarily an advantage
• If (and only if) RBE(target) > RBE(normal tissue), the therapeutic window widens
• Large uncertainties in clinical RBE values
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J.J. Wilkens - TUM Department of Radiation Oncology
Versions of the “local effect model”
Elsässer et al. 2008 IJROBP 71(3) 866-872
target normal tissue normal tissue
1997 2007 2008
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J.J. Wilkens - TUM Department of Radiation Oncology
Most recently: LEM IV
Grün et al. 2012 Phys Med Biol 57 7261-74
optimized with LEM I recalculated with LEM IV
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J.J. Wilkens - TUM Department of Radiation Oncology
Potential validation of RBE models
• Pre-clinical studies in vitro and in vivo
• Clinical studies
• Advance radiobiology to better understand the mechanisms
“From molecules to life”
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J.J. Wilkens - TUM Department of Radiation Oncology
γ-H2AX foci
Focussed protons show elevated RBE
4.5 MeV/u carbon 20 MeV protons 20 MeV protons (single ions) (homogeneous) (sub-µm focussed)
higher RBE than homogeneous protons
Schmid et al. 2012 Phys Med Biol 57 5889-907
5 µm
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J.J. Wilkens - TUM Department of Radiation Oncology
EMRP project: Biologically weighted quantities in radiotherapy (BioQuaRT) A Joint Research Project within the European Metrology Research Programme EMRP Apply micro- and nanodosimetric methods to measure track structure and “radiation quality” define a measureable quantity that is relevant for the biological effectiveness
http://www.ptb.de/emrp/bioquart.html
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J.J. Wilkens - TUM Department of Radiation Oncology
Neutron therapy
• no physical dose advantage • high LET • high RBE gives benefit for
selected patients
depth [mm]
dose
neutrons
gamma Munich: fast neutrons (mean energy: 2 MeV) from nuclear reactor
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J.J. Wilkens - TUM Department of Radiation Oncology
Summary
Biology matters in radiation therapy RBE effects can be additional advantage for ions or neutrons But: • RBE models difficult to validate • better understanding of radiobiological mechanisms
desirable
Foliennummer 1IntroductionThe physical advantage of protons (and ions)Biological effectivenessThe relative biological effectiveness (RBE)RBE-weighted absorbed doseBiological optimization for carbon ionsTechniques for biological optimizationExample: carbon ion planningProblems with RBEVersions of the “local effect model”Most recently: LEM IVPotential validation of RBE modelsFocussed protons show elevated RBEEMRP project: Biologically weighted quantities in radiotherapy (BioQuaRT)�Neutron therapySummary