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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

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ad 4 status report 2010

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

HôpitalUniversitaire de Geneve

German Cancer Research Center, Heidelberg

Max Planck Institute for Nuclear Physics, Heidelberg

University of Montenegro, Podgorica

Biological Effects of Antiprotons

Are Antiprotons a Candidate for Cancer Therapy?

rationale for conformal radiotherapy
Rationale for Conformal Radiotherapy

Dose (and tumor control) are limited due to tolerance of organs at risk

Dose to Target

Better conformity of dose to target enables application of higher doses & higher tumor control without increasing normal tissue complication rate

particle therapy offers reduced integral dose to body
Particle Therapy offersReduced Integral Dose to Body

Particles deposit LESS physical dose in front of the tumor

and NO dose beyond the distal edge of the Bragg peak!

potential clinical advantages
Potential Clinical Advantages?
  • 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!

the ad 4 experiment at cern
The AD-4 Experiment at CERN
  • V-79 Chinese Hamster cells embedded in gelatin
  • Antiproton beam from AD(126 MeV)
  • 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


  • Study cell survival in peak (tumor) and plateau (skin) and compare the results to protons (and carbon ions)
biological analysis method
Biological Analysis Method

Co-60 Dose

RBEplat =

Plateau Dose


RBEpeak =

Co-60 Dose


Peak Dose

  • 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)

Plot “peak” or “plateau” survival vs. absolute dose and compare to 60Co irradiation

comparing dose values needed for


for peak, plateau, and 60Co irradiation:

Relative Biological effectiveness RBE

Example: Protons at Triumf

carbon ions sobp at gsi
Carbon Ions – SOBP at GSI

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
RBE for Carbon Ions

Extract survival vs. dose plot for each depth slice and calculate RBESF=10%

RBEplateau = 1.2 RBEpeak = 2.0 RBE distal = 1.5

RBE Analysis for Antiprotons
  • 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
cern data 2008

note: good control over dose planning for SOBP……..RBEplateau= 1.2 RBEpeak= 1.73 – 2.2

cern data 2009

note: attempt to collect data in tail for RBE analysis…….. difficult task – long irradiation times – very little effect

cern data 2010

Additional data set in Plateau and Peak (preliminary analysis)

……detailed dose calculations and error analysis still ongoing

new beam monitor
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)
  • Dedicated MAPS design to beam monitoring
  • pixel 153×153µm2 squares
  • two 9×9 interdigitedarrays of n-well/p-epi diodes +twoindependentread-out circuits – avoidingdead time
  • In-pixel storage capacitors – choice ~0.5pF or ~5pF 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
Complete Info on Beam Shot

Integral, Width in X and Yfor each shot at a glance

beam shift
Beam Shift!!

Mimotera allows immediate response to Accelerator Problems

Failure of quadrupole was detected and repaired within 1 hour, and

12 hour irradiation of cell samples (half way completed) was saved!

real time imaging simulation
Real Time Imaging - Simulation
  • 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 efficiencye= 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
Results of Simulation

Beam Eye View

Side View

Achievable Precision: +/- 1mm

proof of principle experiment
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)
first experimental realization
First Experimental Realization


Water phantom

  • 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

289.5° Bragg Peak

293.0° distal fall-off


First Results

red: Simulation

blue: Experiment

Distal Edge of Depth Dose Profile is detected

Resolution is limited due to distance from target and pion scattering

monte carlo for clinical beams
Monte Carlo for Clinical Beams

Monte Carlo for Clinical Example: Distance beam to detector = 30 cm

Continuous spill

1 x 109 antiprotons (blue: 1x108)

Detection of distal edge possible with precision of 1 – 2 millimeter

dna damage and repair
DNA Damage and Repair
  • Quantify DNA damage in human cells along and around a 126 MeV antiproton beam at CERN.
  • Investigateimmediate and longer term DNA damage.
  • Investigate non-targeted effects outside the beam path due to secondary particles or bystander signaling.
dna damage and repair assays
DNA Damage and Repair Assays
  • 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

Results g-H2AX Assay

γ-H2AX foci in cells irradiated with up 1.1x109antiprotons in theplateau (blue) or SOBP (red).

results for g h2ax
Results for g-H2AX

SOBP antiprotons generate largerDNA double strand breaks than either plateau antiprotons or X-rays.

60 minutes after radiation no differenceis detected anymore

results micronuclei assay
Results Micronuclei Assay

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 outlook
Summary and Outlook

Achievements 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
Summary and Outlook

Recent Publications

  • Bassler, N., Holzscheiter, M.H., Petersen, J.B., 'Neutron Fluencein Antiproton Radiotherapy, Measurements and Simulations', submitted to ActaOncologica (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 duringantiproton 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 DD 60 (2010) pp. 209- 214
summary and outlook1
Summary and Outlook

Future Work

  • Continue increasing precision of RBE determinationAdd 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, Antiprotons
beam time request
Beam Time Request

2 weeks of 126 MeV (500 MeV/c) antiprotons

  • Survival measurements on V-79 cell linesAugment or complete data set on RBEImprove error analysis
  • Study of DNA damage usingg-H2AX and MNIncreasing statistical significance and complete measurement from 2010 (beam time loss)
  • Liquid ionization chamber measurementsTwo dose rate method on pulsed beams