ad-4 status report 2010

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AD-4 Status Report 2010 Biological Effects of Antiprotons Are Antiprotons a Candidate for Cancer Therapy? January 20, 2011 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 German Cancer Research Center, Heidelberg Max Planck Institute for Nuclear Physics, Heidelberg University of Montenegro, Podgorica 32 Scientists from 10 Institutions

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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 Presentation

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Page 1: AD-4 Status Report  2010

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

Page 2: AD-4 Status Report  2010

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

Page 3: AD-4 Status Report  2010

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

Page 4: AD-4 Status Report  2010

Physical Advantage of Antiprotons

January 20, 2011

Page 5: AD-4 Status Report  2010

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!

Page 6: AD-4 Status Report  2010

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

Page 7: AD-4 Status Report  2010

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

Page 8: AD-4 Status Report  2010

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….

Page 9: AD-4 Status Report  2010

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

Page 10: AD-4 Status Report  2010

• 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

Page 11: AD-4 Status Report  2010

CERN DATA 2008

January 20, 2011

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

Page 12: AD-4 Status Report  2010

CERN DATA 2009

January 20, 2011

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

Page 13: AD-4 Status Report  2010

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

Page 14: AD-4 Status Report  2010

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

Page 15: AD-4 Status Report  2010

Complete Info on Beam Shot

January 20, 2011

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

Page 16: AD-4 Status Report  2010

Online Display of Beam

January 20, 2011

Page 17: AD-4 Status Report  2010

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!

Page 18: AD-4 Status Report  2010

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

Page 19: AD-4 Status Report  2010

Results of Simulation

January 20, 2011

Beam Eye View

Side View

Achievable Precision: +/- 1mm

Page 20: AD-4 Status Report  2010

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

Page 21: AD-4 Status Report  2010

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

Page 22: AD-4 Status Report  2010

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

Page 23: AD-4 Status Report  2010

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

Page 24: AD-4 Status Report  2010

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

Page 25: AD-4 Status Report  2010

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

Page 26: AD-4 Status Report  2010

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).

Page 27: AD-4 Status Report  2010

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

Page 28: AD-4 Status Report  2010

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.

Page 29: AD-4 Status Report  2010

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

Page 30: AD-4 Status Report  2010

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

Page 31: AD-4 Status Report  2010

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

Page 32: AD-4 Status Report  2010

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