Antiproton Cancer Therapy AD- -4/ACE 4/ACE Antiproton Cancer Therapy AD Antiproton Cancer Therapy Science or Fiction? Antiproton Cancer Therapy Science or Fiction? The Biological Effectiveness of Antiproton Annihilation Nzhde Agazaryan 1 , Niels Bassler 2 , Gerd Beyer 3 , John DeMarco 1 , Michael Doser 4 , Oliver Hartley 3 , Michael Holzscheiter 5 , Kei Iwamoto 1 , Sandra Kovacevic 6 , Helge Knudsen 2 , Rolf Landua 4 , Carl Maggiore 5 , Bill McBride 1 , Søren Pape Møller 2 , Jorgen Petersen 7 , Vesna Popovic 6 , Danijela Scepanovic 6 , Tim Solberg 8 , Ulrik Uggerhøj 2 , Sanja Vranjes 9 , Rod Withers 1 , Brad Wouters 10 1 UCLA Medical School, 2 University of Aarhus, 3 Geneva University Hospital 4 CERN, 5 PBar Labs, LLC, 6 University of Montenegro, 7 Aarhus University Hospital 8 University of Nebraska Medical Center, 9 Vinca Institute, 10 University of Maastricht Michael H. Holzscheiter, AD-4 1 SPSC, November 15, 2005
Antiproton Annihilation in Tissue Higher Physical dose Enhanced RBE? Real Time Imaging Michael H. Holzscheiter, AD-4 2 SPSC, November 15, 2005
Antiproton Therapy is based on three claims which need experimental proof: � Antiprotons deliver a higher biological dose for � Antiprotons deliver a higher biological dose for equal effect in the entrance channel than protons or or equal effect in the entrance channel than protons carbon ions carbon ions � The damage outside the beam path due to long and � The damage outside the beam path due to long and medium range annihilation products is small. medium range annihilation products is small. � Antiprotons offer the possibility of real time imaging � Antiprotons offer the possibility of real time imaging using high energy gammas and pions, even at low using high energy gammas and pions, even at low (pre- -therapeutical therapeutical) beam intensity ) beam intensity (pre Michael H. Holzscheiter, AD-4 3 SPSC, November 15, 2005
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) Michael H. Holzscheiter, AD-4 4 SPSC, November 15, 2005
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. Michael H. Holzscheiter, AD-4 5 SPSC, November 15, 2005
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 • RBE peak /RBE plateau Dose (arb. units) (F = ratio of physical dose in peak and plateau region) Michael H. Holzscheiter, AD-4 6 SPSC, November 15, 2005
Antiproton Experiment - Data 1 Surviving Fraction Plateau average (slices 1,2) Peak average (slices 8,8’,9,9’) 0.1 B - 1Gy E - 1Gy C - 2Gy D - 3Gy F - 5Gy J - 25 Gy 0.01 0 2 4 6 8 10 12 14 16 18 20 22 24 Depth (mm) Michael H. Holzscheiter, AD-4 7 SPSC, November 15, 2005
Antiproton - Proton Comparison SUMMARY of BEDR STUDIES Antiprotons Protons Michael H. Holzscheiter, AD-4 8 SPSC, November 15, 2005
Antiproton - Proton Comparison CERN (50 MeV Antiprotons) CERN (50 MeV Antiprotons) TRIUMF (50 MeV MeV Protons) Protons) TRIUMF (50 0 10 Surviving Fraction -1 10 BEDR(20%S) =9.5 Plateau Broad peak average Narrow peak average -2 10 0 5 10 15 20 25 30 Dose (arb. units) Particle Fluence (arb. units) Michael H. Holzscheiter, AD-4 9 SPSC, November 15, 2005
Summary of Clonogenic Experiments � We obtained complete survival curves for 3 and 5 � We obtained complete survival curves for 3 and 5 different dose values respectively in two different dose values respectively in two independent experiments and observed good independent experiments and observed good agreement between the experiments. agreement between the experiments. � An analysis of the data for the BEDR gives a � An analysis of the data for the BEDR gives a result which is significantly higher than the value result which is significantly higher than the value for protons obtained under nearly identical for protons obtained under nearly identical experimental conditions. experimental conditions. � We observe only negligible cell kill outside of the � We observe only negligible cell kill outside of the beam in either the radial or axial (beyond the beam in either the radial or axial (beyond the peak) direction at even the highest dose. peak) direction at even the highest dose. Michael H. Holzscheiter, AD-4 10 SPSC, November 15, 2005
Evidence of low Peripheral Damage 10 1 Distal Radial Sample 0.1 Tube Survival 4.6 GY 13.8 GY 0.01 0.001 1 σ 2 σ 0.0001 0 5 10 15 20 25 30 0 5 10 15 20 Depth [mm] Depth (mm) 3.5 At the highest dose we can see a small 3.0 Comet Assay effect outside the Bragg peak up to few 2.5 mm distance from the direct beam Tail Moment 2.0 1.5 Further work: 1.0 High central dose: Clonogenic studies. DNA damage: COMET, H2AX Assay. 0.5 0.0 0 5 10 15 20 25 30 35 40 Depth in Gelatin [mm] Michael H. Holzscheiter, AD-4 11 SPSC, November 15, 2005
Comparison to Carbon? Using data from Weyrather et al. IJRB 75,1357-1364 (1999) Using SRIM 2003 to calculate dose profile: 35 Peak 30 Peak Plateau Ratio 25 Dose (dE/dx [eV/A]) 31 10.2 3.0 20 Direct experimental RBE 3.9 2.3 1.7 15 BEDR = 5.1 10 Plateau comparison 5 is needed ! 0 0 5 10 15 20 25 30 Range [m Peak Plateau Ratio BEDR = F * RBE Peak /RBE Plateau Dose (dE/dx [eV/A]) 29 4.6 6.3 RBE 3.9 2.3 1.7 F = Dose Ratio Peak to Plateau BEDR = 10 Michael H. Holzscheiter, AD-4 12 SPSC, November 15, 2005
Future Work � The BEDR enhancement is significant !!! What The BEDR enhancement is significant !!! What’ ’s next??? s next??? � � Complete measurement cycle through carbon tests. � Complete measurement cycle through carbon tests. (Experiment at GSI approved – (Experiment at GSI approved – collaboration with Kraft et al.) collaboration with Kraft et al.) � Radiobiological experiments � Radiobiological experiments (Oxygen Enhancement Ratio/Repair) (Oxygen Enhancement Ratio/Repair) � Detailed studies of the peripheral damage. � Detailed studies of the peripheral damage. Α X) , COMET, H2 Α (Clonogenics Clonogenics, COMET, H2 X) ( � Increased efforts on � RBE) � (BEDR � Increased efforts on dosimetry dosimetry (BEDR RBE). . (Experimental work, Model calculations – (Experimental work, Model calculations – LEM) LEM) � Continued development of Monte Carlo capabilities. � Continued development of Monte Carlo capabilities. (MCNPX, GEANT4, SHIELD- -HIT) HIT) (MCNPX, GEANT4, SHIELD � Real time imaging. � Real time imaging. Michael H. Holzscheiter, AD-4 13 SPSC, November 15, 2005
Radiobiological Measurements • The need of direct carbon/antiproton comparison experiments. The question “ How do antiprotons compare to carbon ions, which also show a strong increase in RBE towards the end of range ?” has been raised many times. • Higher energy irradiation: Our initial experiments at CERN were limited by the available beam energy of 50 MeV . This resulted in a very shallow penetration depth into the biological target of about 10 mm, taking into account additional material intercepting the beam, and makes the separation of effects extremely difficult if not impossible . Higher beam energy (15 cm penetration) is needed for the most important experiments! Michael H. Holzscheiter, AD-4 14 SPSC, November 15, 2005
High Energy Beam At 50 MeV kinetic Energy the effective penetration is only 10 mm. The separation between “Peak” and “Plateau” is less than the range of the high LET annihilation products. A clear separation of high and low LET component is not possible! Michael H. Holzscheiter, AD-4 15 SPSC, November 15, 2005
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