ad-4 status report 2010
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AD-4 Status Report 2010. 32 Scientists from 10 Institutions. University of Aarhus University Hospital of Aarhus University of New Mexico, Albuquerque University of Athens Queen’s University Belfast CERN , Geneva Hôpital Universitaire de Geneve - PowerPoint PPT PresentationTRANSCRIPT
AD-4 Status Report 2010Biological Effects of Antiprotons
Are Antiprotons a Candidate for Cancer Therapy?
January 20, 2011
University of AarhusUniversity Hospital of Aarhus
University of New Mexico, AlbuquerqueUniversity of Athens
Queen’s University BelfastCERN, Geneva
Hôpital Universitaire de GeneveGerman Cancer Research Center, Heidelberg
Max Planck Institute for Nuclear Physics, HeidelbergUniversity of Montenegro, Podgorica
32 Scientists from 10 Institutions
Dose to Target
Rationale for Conformal RadiotherapyDose (and tumor control) are limited due to tolerance of organs at risk
Better conformity of dose to target enables application of higher doses & higher tumor control without increasing normal tissue complication rate
January 20, 2011
Particles deposit LESS physical dose in front of the tumor and NO dose beyond the distal edge of the Bragg peak!
Particle Therapy offersReduced Integral Dose to Body
January 20, 2011
Physical Advantage of Antiprotons
January 20, 2011
Potential Clinical Advantages?
January 20, 2011
Each Particle Type shows distinct features
Protons are well known and easy to plan (RBE = 1) which is the reason they are most widely adopted.
Antiprotons have lowest entrance dose for the price of an extended isotropic low dose halo.
Carbon ions have sharpest lateral penumbra but
comparatively higher entrance dose than even protons (no RBE included here), but show forward directed tail due to in beam fragmentation.
Detailed dose plans (including RBE) will need to be developed to assess applicability of particle types for different tumor types and locations!
INGREDIENTS: V-79 Chinese Hamster cells
embedded in gelatin Antiproton beam from AD (126 MeV)
ANALYSIS: Study cell survival in peak (tumor)
and plateau (skin) and compare the results to protons (and carbon ions)
METHOD: Irradiate cells with dose levels to
give survival in the peak is between 0 and 90 %
Slice samples, dissolve gel, incubate cells, and look for number of colonies
The AD-4 Experiment at CERN
January 20, 2011
Example: Protons at Triumf
Plot “peak” and “plateau” survival vs. relative dose to extract the Biological Effective Dose Ratio
BEDR = F • RBEpeak/RBEplateau
(F = ratio of physical dose in peak and plateau region)
Biological Analysis Method
January 20, 2011
RBEpeak =
Co-60 DosePeak Dose =1.15
RBEplat =Co-60 DosePlateau Dose
=1.0
Plot “peak” or “plateau” survival vs. absolute dose and compare to 60Co irradiationcomparing dose values needed for
Iso-Effect for peak, plateau, and 60Co irradiation:
Relative Biological effectiveness RBE
Carbon Ions – SOBP at GSI
January 20, 2011
note: clinical beams with precise dosimetry and fast dose delivery …….. Energy to achieve same clinical relevant depth and form SOBP as at CERN….
RBE for Carbon Ions
January 20, 2011
Extract survival vs. dose plot for each depth slice and calculate RBESF=10%
RBEplateau = 1.2 RBEpeak = 2.0 RBE distal = 1.5
• Physical Dose Calculations requires exact Knowledge of Beam Parameters
• Biological Variability necessitates multiple Independent Experiments under Identical Conditions
• Most important result is NOT Peak-to-Plateau ratio but Variation of RBE with Depth
January 20, 2011
RBE Analysis for Antiprotons
CERN DATA 2008
January 20, 2011
note: good control over dose planning for SOBP…….. RBEplateau = 1.2 RBEpeak = 1.73 – 2.2
CERN DATA 2009
January 20, 2011
note: attempt to collect data in tail for RBE analysis…….. difficult task – long irradiation times – very little effect
January 20, 2011
CERN DATA 2010
1.00E-03
1.00E-02
1.00E-01
1.00E+00
0 20 40 60 80 100 120 140 160
A - 0.5 Gy
B - 4 Gy
C - 3 gy
E - 2.5 Gy
G - 0.77 Gy
K - 2 Gy
J - 1.5 gy
D - Control
F - 1 gy
L - Control
I - 5 Gy
Additional data set in Plateau and Peak (preliminary analysis)……detailed dose calculations and error analysis still ongoing
New Beam Monitor• Purpose: Shot-to-shot monitoring of beam spot
shape, size, and position for precise dose calculations• to replace Gafchromic film, facilitate alignment, and have instant
feed back on beam changes• Solution: Solid state pixel detector (Monolithic Active Pixel Sensor)
January 20, 2011
Dedicated MAPS design to beam monitoring pixel 153×153 µm2 squares two 9×9 interdigited arrays of n-well/p-epi diodes
+ two independent read-out circuits – avoiding dead time
In-pixel storage capacitors – choice ~0.5 pF or ~5 pF to cope with signal range
Mimotera, Massimo Caccia (Universita’ dell’Insumbria Como, Italy)
Long term goal: Measure LET distributions in 2D/3D
Complete Info on Beam Shot
January 20, 2011
Integral, Width in X and Yfor each shot at a glance
Online Display of Beam
January 20, 2011
Beam Shift!!
January 20, 2011
Mimotera allows immediate response to Accelerator Problems
Failure of quadrupole was detected and repaired within 1 hour, and12 hour irradiation of cell samples (half way completed) was saved!
Real Time Imaging - Simulation
January 20, 2011
Use 4 x 3 layers of (virtual) silicon pixel detectors 40x40 cm2 / 5 cm spacing 30 cm from origin
Pixel Resolution s = 100 mm
Track charged pions and photons Overall detector efficiency e = 1% Define vertex as approach of two tracks closer than 2 mm If more than 2 tracks per particle are detected
use meta-center of vertices of any two tracks
Results of Simulation
January 20, 2011
Beam Eye View
Side View
Achievable Precision: +/- 1mm
Proof of Principle Experiment
• Q: How to minimize material and cost• A: Instead of 3 layers use one layer and
look at grazing incidence.
• Q: What detector to use for first test?A: Turn to our friends in ALICE and use one (spare) module of the Alice Silicon Pixel Detector (SPD)
January 20, 2011
First Experimental Realization
January 20, 2011
grazing incidence of pions produce long tracks length distribution changes with angle stopping distribution along z-axis can be inferred Future work: Expansion to 3 - D
pbar
π±
Water phantom
289.5° Bragg Peak 293.0° distal fall-off
January 20, 2011
First Results
Distal Edge of Depth Dose Profile is detectedResolution is limited due to distance from target and pion scattering
red: Simulationblue: Experiment
January 20, 2011
Monte Carlo for Clinical Beams
Monte Carlo for Clinical Example: Distance beam to detector = 30 cmContinuous spill1 x 109 antiprotons (blue: 1x108)
Detection of distal edge possible with precision of 1 – 2 millimeter
DNA Damage and Repair
• Quantify DNA damage in human cells along and around a 126 MeV antiproton beam at CERN.
• Investigate immediate and longer term DNA damage.
• Investigate non-targeted effects outside the beam path due to secondary particles or bystander signaling.
January 20, 2011
DNA Damage and Repair Assays
January 20, 2011
There is more to biology than just clonogenics – especially outside the targeted area:
Immediately after attack on DNA proteins are recruited to the site This event signals cell cycle arrest to allow repair If damage is too extensive to repair programmed cell death (apoptosis) is induced Cells also deficient of cell cycle check point proteins may enter mitosis
(cancer cells are often deficient in repair proteins and continue dividing)
g-H2AX: Phosphorylation of H2AX in the presence of Double Strand Breaks
Micronuclei: Fluorescent detection of micronuclei (parts of whole chromosomes) formed due to DNA damage, which are indicating potential of tumorigenesis
g-H2AX and Micronucleus assays are typically used to study immediate and long term DNA damage respectively
January 20, 2011
Results g-H2AX Assay
γ-H2AX foci in cells irradiated with up 1.1x109 antiprotons in the plateau (blue) or SOBP (red).
Results for g-H2AX
January 20, 2011
SOBP antiprotons generate larger DNA double strand breaks than either plateau antiprotons or X-rays.
60 minutes after radiation no difference is detected anymore
Results Micronuclei Assay
January 20, 2011
Mean number of micronuclei for two replicate experiments for antiproton plateau and SOBP data sets. Sub lethal damage seems to be LET dependent.
Summary and OutlookAchievements 2010• Extended data set on Biological Effect of
Antiprotons for preliminary dose planning studies• Confinement of RBE Enhancement to Bragg peak
only has been confirmed (preliminary analysis)• DNA damage assays for studies of late effects
achieved higher resolution• Fast Beam Monitoring implemented • Real Time Imaging of Stopping Distribution
– Proof of principle experiment performed
January 20, 2011
Recent Publications
• Bassler, N., Holzscheiter, M.H., Petersen, J.B., 'Neutron Fluence in Antiproton Radiotherapy, Measurements and Simulations', submitted to Acta Oncologica (2010)
• Bassler, N., Kantemiris, I., Karaiskos, P., Engelke, J., Holzscheiter, M.H., Petersen, J.B. 2010; Comparison of optimized single and multifield irradiation plans of antiproton, proton, and ion beams, Radiotherapy & Oncology (2010) vol. 95, pp. 87 – 93
• Kantemiris, I., Angelopoulos, A., Bassler, N., Giokaris, N., Holzscheiter, M., Karaiskos, P., Kalogeropoulos, T.E., 'Real-time imaging during antiproton radiotherapy', Phys. Med. Biol. (2010) vol. 55, pp. N1–N9
• J.N. Kavanagh, F.J. Currell, D.J. Timson, M.H. Holzscheiter, N. Bassler, R. Herrmann, G. Schettino; ‘Induction of DNA Damage by Antiprotons for a Novel Radiotherapy Approach’; European Physical Journal D D 60 (2010) pp. 209- 214
January 20, 2011
Summary and Outlook
Summary and OutlookFuture Work• Continue increasing precision of RBE determination
Add more independent data sets (identical conditions)Improving biological protocols and error analysis.Increase data density for sets to stabilize fits
• Detailed dose planning studies on specific cancers• Continue DNA damage studies to assess risk of
secondary primary malignancies (SPM’s)• Develop 2D LET measuring system (mostly off line)• Transfer technology between HIT and AD-4
- Protons, Carbon ions, AntiprotonsJanuary 20, 2011
Beam Time Request2 weeks of 126 MeV (500 MeV/c) antiprotons• Survival measurements on V-79 cell lines
Augment or complete data set on RBEImprove error analysis
• Study of DNA damage using g-H2AX and MNIncreasing statistical significance and complete measurement from 2010 (beam time loss)
• Liquid ionization chamber measurementsTwo dose rate method on pulsed beams
January 20, 2011