The Biological Effectiveness of Antiproton Annihilation

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Antiproton Cancer Therapy Science or Fiction?
Antiproton Cancer Therapy Science towards a
Vision!

The Biological Effectiveness of Antiproton
Annihilation Nzhde Agazaryan1, Niels Bassler2,
Gerd Beyer3, John DeMarco1, Michael Doser4,
Charles Gruhn5, Michael Holzscheiter5, Toshiyasu
Ichioka2, Kei Iwamoto1, Sandra Kovacevic6, Helge
Knudsen2, Rolf Landua4, Carl Maggiore5, Bill
McBride1, Søren Pape Møller2, Jorgen Petersen7,
Vesna Popovic6, Danijela Scepanovic6, Jim
Smathers1, Lloyd Skarsgard8, Tim Solberg1, Ulrik
Uggerhøj2, Sanja Vranjes9, Rod Withers1, Brad
Wouters9 1 UCLA Medical School, 2 University of
Aarhus, 3 Geneva University Hospital 4 CERN, 5
PBar Medical, Inc., 6 University of Montenegro,
7 Aarhus University Hospital 8 British Columbia
Cancer Research Centre, 9 Vinca Institute,
10University of Maastricht
2
Background
"highly concentrated energy transfer is a
desirable and critical element to some
applications such as, for example, the radiation
treatment of smalltumors in sensitive regions of
the body ... R.R. Wilson, Radiology
47 (1946) L. Gray and T. E.
Kalogeropoulos, Radiation Research 97,
(1984) "the ratio of the (physical) dose in the
antiproton stopping peak to that in the plateau
is only about twice that found for protons."
A. H.
Sullivan, Phys. Med. Biol. 30, (1985) Proton
therapy centers exist world wide heavy-ion
therapy is very promising (GSI, HIMAC,HYOGO)
What do antiprotons have to offer?
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Antiproton Annihilation in Tissue
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Antiprotons vs. Protons
Antiprotons generate a complex mixture of
secondary particles. (Only some of which are
captured by Monte Carlo calculations). This
presents a major challenge (as well as an
opportunity) for our research and. ..forces
us at this timeto perform an integral
experiment measuring the overall biological
effect.
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Energy Deposition Antiprotons vs. Protons
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Antiproton Therapy is based on three claims which
need experimental proof

• Antiprotons deliver a higher biological dose for
  equal effect in the entrance channel than protons
• The damage outside the beam path due to long and
  medium range annihilation products is small and
  does not significantly effect treatment planning
• Antiprotons offer the possibility of real time
  imaging using high energy gammas and pions, even
  at low (pre-therapeutical) beam intensity

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Experimental Set-up

• INGREDIENTS
• V-79 Chinese Hamster cells embedded in
  gelatin
• Antiproton beam from AD (46.7 MeV)

• METHOD
• Irradiate cells for prescribed fluencies to
  give dose values where survival in the peak
  is between 0 and 90
• Slice samples, dissolve gel, incubate cells,
  and look for number of colonies

• ANALYSIS
• Study survival vs. dose in peak and plateau
  and compare to protons
• (and carbon ions)

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Biological Analysis Technique

• Irradiate sample tube with living cells
  suspended in gel.
• Slice sample tube in ?1 mm slices and
  determine survival fraction for each slice.

• Repeat for varying (peak) doses.

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Biological Analysis Technique

• Calculate plateau survival using slices 1 4.
• Determine peak survival from slice 8 and 9.

• Plot peak and plateau survival vs. relative
  dose (Plateau dose, particle fluence, etc.)
  and extract the Biological Effective Dose
  Ratio
• BEDR F RBEpeak/RBEplateau
• (F ratio of physical dose in peak
  and plateau region)

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Antiproton Experiment - Data
Surviving Fraction
B - 1Gy
E - 1Gy
C - 2Gy
D - 3Gy
F - 5Gy
J - 25 Gy
Depth (mm)
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Antiproton Experiment - Results
BEDR Analysis
0
10
-1
BEDR(20S)9.2 - Broad peak
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Surviving Fraction
BEDR(20S)9.8 - Narrow peak
Plateau
Broad peak average
Narrow peak average
-2
10
0
5
10
15
20
25
30
Particle Fluence (arb. units)
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Antiproton - Proton Comparison
TRIUMF (50 MeV Protons)
0
10
Surviving Fraction
-1
10
BEDR(20S)9.2 - Broad peak
BEDR(20S)9.8 - Narrow peak
Plateau
Broad peak average
Narrow peak average
-2
10
0
5
10
15
20
25
30
Particle Fluence (arb. units)
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Summary of Clonogenic Experiments

• We obtained complete survival curves for 5
  different doses. The results compare well with a
  previous experiment yielding a limited data set.
• An analysis of the data for the BEDR gives a
  result which is significantly higher than the
  value for protons obtained under nearly identical
  experimental conditions.
• We observe only negligible cell kill outside of
  the beam in either the radial or axial (beyond
  the peak) direction at even the highest dose.

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Antiproton - Proton Comparison
SUMMARY of BEDR STUDIES
Protons
Antiprotons
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Evidence of low Peripheral Damage
Distal
Radial
At the highest dose we can see a small effect
outside the Bragg peak up to few mm distance
from the direct beam Alternative assay Look for
DNA damage
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The COMET Assay
The comet assay is a gel electrophoresis method
used to visualize and measure DNA strand breaks
in individual cells using microscopy
Automated Analysis on individual cells

Statistical accuracy through analysis of gt 100
cells per sample
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The COMET Assay Early Results

• Cell sample irradiated with 15 Gy
• Slices (0.5 mm and 1 mm) for plateau peak perip
  heral (distal)
• COMET Assay performed by the Inst. for Occup.
  Medicine, Zagreb
• No detectable damage above control sample

PRELIMINARY
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Comparison to Carbon?
Using data from Weyrather et al. IJRB
75,1357-1364 (1999)
Using SRIM 2003 to calculate dose profile
Peak
Direct experimental comparison is needed !
Plateau
BEDR F RBEPeak/RBEPlateau F Dose Ratio
Peak to Plateau
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Additional Work

• The BEDR enhancement is significant.
• NEXT STEPS
• Detailed studies of the peripheral damage due to
  the medium and long range annihilation products.
• Increased efforts on dosimetry in the periphery
  to the beam as well as in the beam.
• Continued development of Monte Carlo
  capabilities.(MCNPX and GEANT currently do not
  properly include recoil ions above M 4).
• Real time imaging.
• Deeper penetration, dose painting, etc.

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Future Directions
2005 Direct comparison with heavy ions (HIMAC,
RIKEN)

• 2006 RD towards therapeutic relevant
  situations Upgrades of experimental
  set-up at the AD
• Development of beam delivery and energy
  modulation higher energy extraction (10 to 15
  cm range) 1 mm focus, scanning possibility
  (Complete DEM line)
• Real time imaging of shaped target Implement
  semi-slow extraction (106 107/second)?
• Biological experiments using spread-out Bragg
  peaks closer to actual tumor situations (?
  ? 3 - 5 cm) 2 x 108 pbars deliver 1 Gy to 1 cc
  tumor (10 shots or 15 minutes) (possibilities
  to increase intensity per shot?)

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Its all about Collateral Damage
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Real time Imaging
Initial Imaging tests using amorphous silicon
detectors with fast read-out
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Peripheral Damage Neutron Dosimetry
Placement of 6Li and 7Li TLD chipsat 30 to 120
mm from annihilation volume Total dose in Peak
7 GyDose seen at 30 mm lt 2 cGy
PRELIMINARY
Additional dose in 6Li fromthermal neutrons
only Additional measurements toestablish neutron
spectrumin preparation
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