1. Low-dose vs. high-dose effects
New schedule of fractionation and their impact on local control and survival
Low-dose vs. high-dose effects
Marco Durante
Jan. 21, 2012
PARTNER - EU FP 7

2. Contents Short summary of fractionation
High-dose vs. low dose radiobiology
Nontargeted effects
High- and low doses for heavy ions
Fractionation in heavy-ion treatment plans in Japan and Europe
Jan. 21, 2012
PARTNER - EU FP 7

3. 1. Recapitulation
Jan. 21, 2012
PARTNER - EU FP 7

4. 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
Jan. 21, 2012
PARTNER - EU FP 7

5. Jan. 21, 2012
PARTNER - EU FP 7

6. Early- and late-responding tissues
a/b~10
1<a/b<7
Jan. 21, 2012
PARTNER - EU FP 7

7. Isoeffect doses for early and late normal tissue damage
Accelerated repopulation in mouse tumors
Gordon Steel, 2002
Jan. 21, 2012
PARTNER - EU FP 7

8. 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

9. 2. Is high-dose radiobiology different from low-dose radiobiology?
Jan. 21, 2012
PARTNER - EU FP 7

10. Different gene expression after low- and high-doses
p53 dominates at high doses, HNF4A at low doses
Slide courtesy of Sally Amundson, Columbia University
Jan. 21, 2012
PARTNER - EU FP 7

11. Inflammation response
epithelial cells
leukocytes
endothelial cells
macrophages/
dentritic cells
fibroblasts
[courtesy of Claudia Fournier]
Jan. 21, 2012
PARTNER - EU FP 7

12. Pro-inflammatory response (high-doses)
lymphocytes
macrophages
acute phase reactions:
acute phase proteins, fever, tiredness, low appetite
endothelial effects:
leukocyte adherence, increase of adhesion molecules
fibroblast effects:
proliferation, proteases, collagenases
activation
phagocytosis
NO-induction
IL-1
TNF-α
endothelial cells
endothelial cells
endothelial cells
leukocyte
blood vessel
rolling
leukocyte
leukocyte
increase of
adhesion
molecules
adhesion
endothelial cells
endothelial cells
endothelial cells
leukocyte
[Rödel et al. 2001, LD-RT: molecular and functional aspects]
[Feghali et al. 1997, cytokines in acute and chronic inflammation]
migration
Jan. 21, 2012
PARTNER - EU FP 7

13. Anti-inflammatory response (low doses)
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
lymphocytes
macrophages
suppression:
proliferation,
ROS, NO
TGF-β
endothelial cells
endothelial cells
endothelial cells
leukocyte
blood vessel
inhibition of
adhesion
leukocyte
leukocyte
decrease of
adhesion
molecules
endothelial cells
endothelial cells
endothelial cells
[Rödel et al. 2001, LD-RT: molecular and functional aspects][Rödel et al. 2004, Dose dependent induction...of NF-κB...]
Jan. 21, 2012
PARTNER - EU FP 7

14. pro-inflammatory cytokines
Basic idea of anti-inflammatory mechanism
low dose IR
epithelial cells
epithelial cells
epithelial cells
epithelial cells
fibroblasts
fibroblasts
fibroblasts
apoptotic cells
cytokines
e.g. TGF-β
macrophages DC
suppression of:
proliferation
pro-inflammatory cytokines
NO production
[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

15. 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?
Jan. 21, 2012
PARTNER - EU FP 7

16. 3. Nontargeted effects in therapy
Prise & O’Sullivan, Nat. Rev. Cancer 2009
Jan. 21, 2012
PARTNER - EU FP 7

17. Medulloblastoma in Ptch-1 radiosensitive mice (Mancuso et al
Medulloblastoma in Ptch-1 radiosensitive mice (Mancuso et al., PNAS 2008)
Jan. 21, 2012
PARTNER - EU FP 7

18. Radiation Absorbed Dose
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 Mortality
Newhauser & Durante,
Nature Rev. Cancer 2011
Risk of SMN Incidence
Jan. 21, 2012
PARTNER - EU FP 7

19. Newhauser & Durante, Nat. Rev. Cancer 2011
Jan. 21, 2012
PARTNER - EU FP 7

20. 4. Is there a “low dose” of heavy ions?
X-rays
2 keV/mm
2 Gy
177 MeV/u Fe-ions
335 keV/mm
2 Gy, 3.7*106 /cm2
4.1 MeV/u Cr-ions
3160 keV/mm
20.3 Gy, 4*106 /cm2
same dose
same fluence
Jan. 21, 2012
PARTNER - EU FP 7

21. Beamline live microscopy
Jan. 21, 2012
PARTNER - EU FP 7

22. Live cell imaging of heavy ion traversals
High energy Fe-ions
Low energy Ni-ions, human cells, GFP-APTX
GFP-NSBS1
Jakob et al., Proc. Natl. Acad. Sci. USA 2009
GFP-XRCC1
Jan. 21, 2012
PARTNER - EU FP 7

23. 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 b-excision repair pathways)
Jakob et al.
Nucl. Acids Res. 2011
Jan. 21, 2012
PARTNER - EU FP 7

24. From DNA to chromosomes: heavy-ion induced rearrangements
Jan. 21, 2012
PARTNER - EU FP 7

25. Chromosomal rearrangements in normal human fibroblasts exposed to a single 12C-ion traversal
gH2AX
DAPI
Jan. 21, 2012
C. Fournier & S. Ritter
PARTNER - EU FP 7

26. 5. Fractionation on heavy-ion TPS
Jan. 21, 2012
PARTNER - EU FP 7

27. Durante & Loeffler, Nature Rev Clin Oncol 2010 Potential advantages. 2 8 6 4
Tumor
Normal tissue
Relative dose
Potential advantages 5 1 2
Depth (mm)
Energy
LET
Dose
RBE
OER
Cell-cycle
dependence
Fractionation
Angiogenesis
Cell migration
high low
low high
low high
 > 1
 < 3
Increased Decreased
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

28. 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.
Jan. 21, 2012
PARTNER - EU FP 7

29. Beam Delivery System: GSI/HIT/CNAOx y z
Active scanning technique
3D shapes of physical depth dose distributions, individually optimized according to clinical requirements
Jan. 21, 2012
PARTNER - EU FP 7

30. Beam Delivery System: HIMAC/Hyogo/Gunma
Range Shifter
Bolus
Ridge Filter
Multileaf Collimator
Passive beam shaping technique
Jan. 21, 2012
PARTNER - EU FP 7

31. RBE and GyE 6.4 4.8 3 2.8 2.5 GyE=GyxRBE Sv=GyxQ > GyE
Jan. 21, 2012
PARTNER - EU FP 7

32. RBE-Weighted Dose: HIMAC
HIMAC: Basis: Long term experience in clinical trials with neutrons at NIRS
Wheel of 8 Fixed Ridge Filters
Empirical Results for Neutrons:
Clinical determined RBE ≈ 3.0
Clinically
Prescribed Dose
RBE = 3.0
Scaling of the complete physical depth dose profile to ensure:
Scaled
Physical Depth
Dose Profile
of Carbon Ions
= 3.0
Clinically Prescribed Dose
Phys. Dose at
Neutron-Equ. Pos.
Neutron-Equivalent Position
Jan. 21, 2012
PARTNER - EU FP 7

33. Conversion Method: HIMAC LEM
LEM Prescribed RBE-Weighted Dose 1.
HIMAC Prescribed RBE-Weighted Dose
RBE = 3.0
RBE-Weighted Dose Distribution Estimated by LEM / TRiP
Simulated HIMAC Physical Depth Dose Distribution
RBE
table
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)
Jan. 21, 2012
PARTNER - EU FP 7

34. Conversion Method: HIMAC LEM
LEM Prescribed RBE-Weighted Dose
HIMAC Prescribed RBE-Weighted Dose
RBE = 3.0
RBE-Weighted Dose Distribution Estimated by LEM / TRiP
Simulated HIMAC Physical Depth Dose Distribution
RBE 2.
table
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)
Jan. 21, 2012
PARTNER - EU FP 7

35. Conversion Method: HIMAC LEM
LEM Prescribed RBE-Weighted Dose
HIMAC Prescribed RBE-Weighted Dose
RBE = 3.0
RBE-Weighted Dose Distribution Estimated by LEM / TRiP
Simulated HIMAC Physical Depth Dose Distribution
RBE 3.
table
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)
Jan. 21, 2012
PARTNER - EU FP 7

36. Conversion Method: HIMAC LEM
LEM Prescribed RBE-Weighted Dose 4.
HIMAC Prescribed RBE-Weighted Dose
RBE = 3.0
RBE-Weighted Dose Distribution Estimated by LEM / TRiP
Simulated HIMAC Physical Depth Dose Distribution
RBE
table
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)
Jan. 21, 2012
PARTNER - EU FP 7

37. Dependence of the conversion factor from the dose and the SOBP position
Details: LEM IV
LEM IV
Proximal End
Median
Distal End
Conversion Factors
Jan. 21, 2012
PARTNER - EU FP 7

38. Conversion factors for different tumor sizes
Dependence on SOBP width: LEM IV
LEM IV
20 mm SOBP …
120 mm SOBP
Conversion Factors
Jan. 21, 2012
PARTNER - EU FP 7

39. Summary
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
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

40. Biophysics Department
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)
Thank you very much!
Jan. 21, 2012
PARTNER - EU FP 7