jan. 21, 2012 partner - eu fp 7 low-dose vs. high-dose effects marco durante new schedule of...
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Jan. 21, 2012 PARTNER - EU FP 7
Low-dose vs. high-dose effects
Marco Durante
New schedule of fractionation and their impact on local control and survival
Jan. 21, 2012 PARTNER - EU FP 7
Contents
1. Short summary of fractionation
2. High-dose vs. low dose radiobiology
3. Nontargeted effects
4. High- and low doses for heavy ions
5. Fractionation in heavy-ion treatment plans in Japan and Europe
Jan. 21, 2012 PARTNER - EU FP 7
1. Recapitulation
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Fractionation (Recovery)
Surviving cells behave like unirradiated cells, if dose is split and time for recovery is given
Fractionation (Protraction)reduces the effect of total dose
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Jan. 21, 2012 PARTNER - EU FP 7
Early- and late-responding tissues
~10
<7
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Accelerated repopulation in mouse tumors
Isoeffect doses for early and late normal tissue damage
Gordon Steel, 2002
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Variation in Radiation Sensitivity Among Adult Human Organs
Approximate Tolerance Dose (TD) beyond which there is a high probability of delayed injury, e.g. 5% clinical injury within 5 years after exposure.
Jan. 21, 2012 PARTNER - EU FP 7
2. Is high-dose radiobiology different from low-dose radiobiology?
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• Different gene expression after low- and high-doses
• p53 dominates at high doses, HNF4A at low doses
• Slide courtesy of Sally Amundson, Columbia University
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Inflammation response
epithelial cells
endothelial cells
fibroblasts
macrophages/dentritic cells
leukocytes
[courtesy of Claudia Fournier]
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endothelial cells
adhesion
endothelial cells endothelial cells
leukocyte
leukocyte
leukocyte
leuk
ocyte
rolling
migration
IL-1TNF-α
increase of adhesion molecules
lymphocytesmacrophages
activation
• acute phase reactions:• acute phase proteins, fever, tiredness, low appetite
• endothelial effects:• leukocyte adherence, increase of adhesion molecules
• fibroblast effects:• proliferation, proteases, collagenases
endothelial cells endothelial cells endothelial cells
blood vessel
phagocytosisNO-induction
[Rödel et al. 2001, LD-RT: molecular and functional aspects] [Feghali et al. 1997, cytokines in acute and chronic inflammation]
Pro-inflammatory response (high-doses)
Jan. 21, 2012 PARTNER - EU FP 7
endothelial cells
inhibition of adhesion
endothelial cells endothelial cells
leukocyte
leukocyte
leukocyteTGF-β
decrease of adhesionmolecules
lymphocytes macrophages
suppression:proliferation,
ROS, NO
• induction of apoptosis in various cell types• inhibition of pro-inflammatory cytokine production• endothelial effects:
• suppression of proliferation• fibroblast effects:
• proliferation, ECM components e.g. collagen
endothelial cells endothelial cells endothelial cells
blood vessel
[Rödel et al. 2001, LD-RT: molecular and functional aspects][Rödel et al. 2004, Dose dependent induction...of NF-κB...]
Anti-inflammatory response (low doses)
Jan. 21, 2012 PARTNER - EU FP 7
epithelial cells epithelial cells epithelial cells
fibroblasts fibroblasts fibroblasts
epithelial cells
macrophages DC
low dose IR
cytokinese.g. TGF-β
suppression of:proliferation
pro-inflammatory cytokinesNO production
Basic idea of anti-inflammatory mechanism
apoptotic cells
apoptotic cells
[Rödel et al.2001, LD-RT: molecular and functional aspects"][Flatscher 2006,"efects of alpha radiation on...langerhans cells"][Herrmann et al. 1997, immunosuppressive effects of apoptotic cells"]
Jan. 21, 2012 PARTNER - EU FP 7
Phoenix rising (Huang et al. Nat. Med. 2011)
• Dead cells get absorbed by “scavenger” cells such as macrophages
• However, studies that originated more than 40 years ago have indicated that tumors respond to radiotherapy by initiating a process called “accelerated repopulation”.
• New studies have now clarified that this is caused by caspase 3, a cysteine protease involved in the “execution” phase of cellular apoptosis,
• Caspase-3 activates the Ca-independent phosholipase A2 (iPA2)
• iPA2 activation increases the production of arachidonic acid (AA), whose downstream eicosanoid derivatives (i.e. prostaglandin E2), stimulate tumor growth and stem cell proliferation.
• What is the dose/fractionation dependence of this mechanism?
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3. Nontargeted effects in therapy
Prise & O’Sullivan, Nat. Rev. Cancer 2009
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Medulloblastoma in Ptch-1 radiosensitive mice (Mancuso et al., PNAS 2008)
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Secondary Malignant Neoplasms (SMN) in particle therapy
Comparison of relative radiation dose distribution with the corresponding relative risk distribution for radiogenic second cancer incidence and mortality. This 9-year old girl received craniospinal irradiation for medulloblastoma using passively scattered proton beams. The color scale illustrates the difference for absorbed dose, incidence and mortality cancer risk in different organs.
Radiation Absorbed Dose
Risk of SMN Incidence
Risk of SMN Mortality
Newhauser & Durante,
Nature Rev. Cancer 2011
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Newhauser & Durante, Nat. Rev. Cancer 2011
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4. Is there a “low dose” of heavy ions?
177 MeV/u Fe-ions335 keV/mm
2 Gy, 3.7*106 /cm2
4.1 MeV/u Cr-ions3160 keV/mm
20.3 Gy, 4*106 /cm2
X-rays2 keV/mm
2 Gy
same dose same fluence
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Beamline live microscopy
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Live cell imaging of heavy ion traversals
Low energy Ni-ions, human cells, Low energy Ni-ions, human cells, GFP-APTXGFP-APTX
High energy Fe-ionsHigh energy Fe-ions
Jakob et al., Proc. Natl. Acad. Sci. USA 2009
GFP-NSBS1
GFP-XRCC1
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Recruitment of XRCC1 to heterochromatin and euchromatin after exposure of mouse embryo fibroblasts to heavy ions
X-ray repair complementing
defective in Chinese
hamster cells 1 (SSB and -
excision repair
pathways)
Jakob et al.Nucl. Acids Res. 2011
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From DNA to chromosomes:heavy-ion induced rearrangements
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Chromosomal rearrangements in normal human fibroblasts exposed to a single 12C-ion traversal
C. Fournier & S. Ritter
H2AXDAPI
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5. Fractionation on heavy-ion TPS
High tumor dose, normal tissue sparing
Effective for radioresistant tumors
Effective against hypoxic tumor cells
Increased lethality in the target because cells in radioresistant (S) phase are sensitized
Fractionation spares normal tissue more than tumor
Reduced angiogenesis and metastatization
Potential advantages
Energy
LET
Dose
RBE
OER
Cell-cycledependence
Fractionationdependence
Angiogenesis
Cell migration
1.2
1.0
0.8
0.6
0.4
0.2
0.00 50 100 150 200
Tumor
Normal tissue
high low
low high
low high
1 > 1
3 < 3
high low
high low
Increased Decreased
Increased Decreased
Rel
ativ
e d
ose
Depth (mm)
Durante & Loeffler,
Nature Rev Clin Oncol 2010
Jan. 21, 2012 PARTNER - EU FP 7
Heavy ion therapy
• HIMAC (Heavy Ion Medical Accelerator)• NIRS (National Institute for Radiological Science)• Since 1994 over 5,000 patient treated with C-ions
• LEM (Local Effect Model) / TRiP (TReatment planning for Particles)• GSI (Helmholtzzentrum für Schwerionenforschung) and other centers• Since 1997 over 440 patient treated with C-ions
• HIMAC / LEM• Very different beam delivery systems• Very different specifications of RBE-weighted dose
A common basis for mapping between center-related beam parameters and clinical outcome is essential.
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Beam Delivery System: GSI/HIT/CNAO
x yz
Active scanning technique
• 3D shapes of physical depth dose distributions, individually optimized according to clinical requirements
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Beam Delivery System: HIMAC/Hyogo/Gunma
HIMAC:
Ridge Filter
Range Shifter
Multileaf Collimator
Bolus
Passive beam shaping technique
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RBE and GyE
2.5
2.8
3
4.8
6.4
GyE=GyxRBE
Sv=GyxQ > GyE
Jan. 21, 2012 PARTNER - EU FP 7
Empirical Results for Neutrons:
• Clinical determined RBE ≈ 3.0
Scaled
Physical Depth
Dose Profile
of Carbon Ions
Scaling of the complete physical depth dose profile to ensure:
= 3.0Clinically Prescribed Dose
Phys. Dose atNeutron-Equ. Pos.
Clinically
Prescribed Dose
RBE = 3.0
Neutron-Equivalent Position
RBE-Weighted Dose: HIMAC
HIMAC: Basis: Long term experience in clinical trials with neutrons at NIRS Wheel of 8 Fixed Ridge Filters
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Conversion Method: HIMAC LEM
HIMAC Prescribed RBE-Weighted
Dose
RBE = 3.0
LEM / TRiP
RBE-Weighted Dose Distribution
Estimated by LEM / TRiP
1.
1. HIMAC prescribed RBE-weighted dose
2. Simulation of the related HIMAC physical depth dose distribution (in TRiP)
3. Estimation of the RBE-weighted dose distribution by LEM / TRiP
4. LEM prescribed RBE-weighted dose (median)
RBE
LEM Prescribed RBE-Weighted
Dose
Simulated HIMAC Physical Depth Dose Distribution
table
Jan. 21, 2012 PARTNER - EU FP 7
HIMAC Prescribed RBE-Weighted
Dose
RBE = 3.0
LEM / TRiP
RBE-Weighted Dose Distribution
Estimated by LEM / TRiP
1. HIMAC prescribed RBE-weighted dose
2. Simulation of the related HIMAC physical depth dose distribution (in TRiP)
3. Estimation of the RBE-weighted dose distribution by LEM / TRiP
4. LEM prescribed RBE-weighted dose (median)
RBE
LEM Prescribed RBE-Weighted
Dose
Simulated HIMAC Physical Depth Dose Distribution
table2.
Conversion Method: HIMAC LEM
Jan. 21, 2012 PARTNER - EU FP 7
HIMAC Prescribed RBE-Weighted
Dose
RBE = 3.0
LEM / TRiP
RBE-Weighted Dose Distribution
Estimated by LEM / TRiP
1. HIMAC prescribed RBE-weighted dose
2. Simulation of the related HIMAC physical depth dose distribution (in TRiP)
3. Estimation of the RBE-weighted dose distribution by LEM / TRiP
4. LEM prescribed RBE-weighted dose (median)
RBE
LEM Prescribed RBE-Weighted
Dose
Simulated HIMAC Physical Depth Dose Distribution
table
Conversion Method: HIMAC LEM
3.
Jan. 21, 2012 PARTNER - EU FP 7
HIMAC Prescribed RBE-Weighted
Dose
RBE = 3.0
LEM / TRiP
RBE-Weighted Dose Distribution
Estimated by LEM / TRiP
1. HIMAC prescribed RBE-weighted dose
2. Simulation of the related HIMAC physical depth dose distribution (in TRiP)
3. Estimation of the RBE-weighted dose distribution by LEM / TRiP
4. LEM prescribed RBE-weighted dose (median)
RBE
LEM Prescribed RBE-Weighted
Dose
Simulated HIMAC Physical Depth Dose Distribution
table
Conversion Method: HIMAC LEM
4.
Jan. 21, 2012 PARTNER - EU FP 7
Median
Proximal End
Distal End
Conversion Factors
Dependence of the conversion factor from the dose and the SOBP position
LEM IVDetails: LEM IV
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Conversion factors for different tumor sizes
LEM IV
• 20 mm SOBP
• …• 120 mm SOBP
Conversion Factors
Dependence on SOBP width: LEM IV
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Significant differences between HIMAC- and LEM-based RBE-weighted doses:
• Conversion factors between 0.4 and 2.0 for prescribed doses from 1 Gy (RBE) to 60 Gy (RBE)
• Conversion factor decreases monotonically with increasing prescribed dose/fraction
Summary
For interpretation and comparison of clinical trials performed using HIMAC- and LEM-bases RBE-weighted doses, it is of extreme importance to consider these conversion factors.
Steinsträter et al. Int. J. Radiat. Oncol. Biol. Phys. 2012
Jan. 21, 2012 PARTNER - EU FP 7
M. Durante (Director)
G. Kraft (Helmholtz Professor)
G. Taucher-Scholz (DNA damage)
B. Jakob (DNA repair)
S. Ritter (Chromosome aberrations)
C. Fournier (Late effects)
W. Kraft-Weyrather (Clinical radiobiology)
M. Scholz (Biophysical modelling)
M. Krämer (Treatment planning)
C. Bert (Moving targets)
C. La Tessa (Dosimetry)
http://www.gsi.de/forschung/bio/