jan. 21, 2012 partner - eu fp 7 low-dose vs. high-dose effects marco durante new schedule of...

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

Low-dose vs. high-dose effects

Marco Durante

New schedule of fractionation and their impact on local control and survival


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


1. Recapitulation


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


Early- and late-responding tissues

~10

<7


Accelerated repopulation in mouse tumors

Isoeffect doses for early and late normal tissue damage

Gordon Steel, 2002


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.


2. Is high-dose radiobiology different from low-dose radiobiology?


• Different gene expression after low- and high-doses

• p53 dominates at high doses, HNF4A at low doses

• Slide courtesy of Sally Amundson, Columbia University


Inflammation response

epithelial cells

endothelial cells

fibroblasts

macrophages/dentritic cells

leukocytes

[courtesy of Claudia Fournier]


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)


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)


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"]


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?


3. Nontargeted effects in therapy

Prise & O’Sullivan, Nat. Rev. Cancer 2009


Medulloblastoma in Ptch-1 radiosensitive mice (Mancuso et al., PNAS 2008)


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


Newhauser & Durante, Nat. Rev. Cancer 2011


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


Beamline live microscopy


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


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


From DNA to chromosomes:heavy-ion induced rearrangements


Chromosomal rearrangements in normal human fibroblasts exposed to a single 12C-ion traversal

C. Fournier & S. Ritter

H2AXDAPI


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


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.


Beam Delivery System: GSI/HIT/CNAO

x yz

Active scanning technique

• 3D shapes of physical depth dose distributions, individually optimized according to clinical requirements


Beam Delivery System: HIMAC/Hyogo/Gunma

HIMAC:

Ridge Filter

Range Shifter

Multileaf Collimator

Bolus

Passive beam shaping technique


RBE and GyE

2.5

2.8

3

4.8

6.4

GyE=GyxRBE

Sv=GyxQ > GyE


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


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



Dose

RBE = 3.0

LEM / TRiP







RBE


Dose


table2.




Dose

RBE = 3.0

LEM / TRiP







RBE


Dose


table


3.



Dose

RBE = 3.0

LEM / TRiP







RBE


Dose


table


4.


Median

Proximal End

Distal End

Conversion Factors

Dependence of the conversion factor from the dose and the SOBP position

LEM IVDetails: LEM IV


Conversion factors for different tumor sizes

LEM IV

• 20 mm SOBP

• …• 120 mm SOBP

Conversion Factors

Dependence on SOBP width: LEM IV


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


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/

jan. 21, 2012 partner - eu fp 7 low-dose vs. high-dose effects marco durante new schedule of...

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