AD-4 Status Report 2009Biological Effects of Antiprotons

Are Antiprotons a Candidate for Cancer Therapy?

January 19, 2010

University of AarhusUniversity Hospital of AarhusUniversity of New Mexico, AlbuquerqueUniversity of AthensQueen’s University BelfastVinca Institute for Nuclear Physics, BelgradeCERN, GenevaHôpital Universitaire de GeneveGerman Cancer Research Center, HeidelbergMax Planck Institute for Nuclear Physics, HeidelbergUniversity of California, Los AngelesUniversity of Montenegro, Podgorica

35 Scientists from 12 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 19, 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 19, 2010

Monte Carlo Comparisons for different Particles

MCNPX

FLUKA

GEANT

SHIELD HIT

.

.

Beware ofGIGO!

We need Experiments

January 19, 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 19, 2010

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 19, 2010

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 19, 2010

note: clinical beams with precise dosimetry and fast dose delivery …….. Higher energy to achieve clinical relevant depth and form SOBP….

RBE for Carbon Ions

January 19, 2010

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

RBEplateau = 1.2 RBEpeak = 2.0 RBE distal = 1.5

ANTIPROTONSCERN DATA 2006

January 19, 2010

note: insufficient data due to dose error (beam spot size) …….

CERN DATA 2007

January 19, 2010

note: poor quality of SOBP due to degrading mechanism …….

CERN DATA 2008

January 19, 2010

note: better control over dose planning for SOBP……..RBE = 1.2 RBE = 1.73 – 2.2 RBE = 1.52 (???)

CERN DATA 2009

January 19, 2010

note: attempt to collect data in tail for RBE analysis……..

Combining/Comparing Data ?

January 19, 2010

Different ratios of low LET/high LET in SOBP inhibit combination of data except for plateau

January 19, 2010

RBE for Antiprotons(Plateau)

RBEplat = 1.25

Good agreement with Monte Carlo Results (Bassler, Holzscheiter; Acta Oncologica, 2009; 48: 223 226)

January 19, 2010

RBE for Antiprotons(Peak)

RBEPeak = 2.25

RBEplat = 1.25

Need more data points for fit. Need repeat experiments for statistics.But everything points towards “step-function” for RBE vs. depth for antiprotons

Potential Clinical Advantages?

January 19, 2010

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!

How to Tell the Difference?

January 19, 2010

Dose Volume Histograms (DVH’s) show what percentage of the volume of interest receiveswhat level of dose. These are the standard figures of merit for dose planners.

Antiprotons produce less radiation load to healthy tissue than protons or carbon ions !!!(carbon ions and antiprotons considered biological identical)

Single field

two opposing fields

DNA Damage Assays

January 19, 2010

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)

-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 indicating potential of tumorigenesis

-H2AX and Micronucleus assays are typically used to study immediate and long term DNA damage respectively

January 19, 2010

Results -H2AX Assay

Results Micronuclei Assay

January 19, 2010

Liquid Ionization Chambers

January 19, 2010

Tetramethylsilane (TMS)

Si)CH( 43

Isooctane

C8H18

Higher density of liquid medium than air provides: Higher sensitivity Allows smaller dimensions Measurement of steep field gradients Useable at very low dose rate

Higher density means higher recombination losses General recombination Ions generated by different incident particles recombine Dose rate dependence Initial (columnar) recombination Ions created by same incident particle recombine depends on ionization density along track can be used to determine Linear Energy Transfer (LET)

Columnar recombination is described by Jaffe Theory Understand relationship of columnar and general recombination ongoing experiments at AD-4 and Umeo Microtron

January 19, 2010

LIC ResultsMeasure charge collected for different voltages

in Plateauin Bragg Peak2 mm and 5 mm distal to Bragg Peak

Asymptotic slope is indicationof Linear Energy Transfer

Jaffe Theory can be usedto calculate flux averaged LET

Results

This work: LETantiproton BP = 9.0 keV/mLETproton(173 MeV) BP = 3.2 keV/m

Kempe et al.LETproton(202 MeV) BP = 3.6 keV/m

New Beam Monitor• Purpose: Shot-to-shot monitoring of beam spot

shape, size, and position• to replace Gafchromic film, facilitate alignment, and have

instant feed back on beam changes• Solution: Solid state pixel detector (Monolithic Active Pixel Sensor)

January 19, 2010

Dedicated MAPS design to beam monitoringDedicated 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 electronics – 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

First Results – All Single Shots

January 19, 2010

Single shot pixel matrixx – y slices through several shots to check stability of beam

Lego representation of beam profile

Initial test of Mimotera in AD-4 (2 hours of beam time) Joint effort to quantify response to intensity and LET while using Mimotera as online beam monitor Additional tests and R&D at HIT to certify detector for medical use

Real Time Imaging - Simulation

January 19, 2010

Use 4 x 3 layers of (virtual) silicon pixel detectors 40x40 cm2 / 5 cm spacing 30 cm from origin

Pixel Resolution = 100 m

Track charged pions and photons Overall detector efficiency= 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 19, 2010

Beam Eye View

Side View

Achievable Precision: +/- 1mm(Accepted for publication in Phys. Med. Biol.)

First Experimental Realization

• 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 19, 2010

First Experimental Realization

January 19, 2010

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

Summary and OutlookAchievements• Initial Results on Biological Effect of Antiprotons can

be used for preliminary Dose Planning Studies• RBE Enhancement confined to Bragg Peak only• DNA damage assays for studies of late effects• Initial Steps towards Fast Beam Monitoring and

Real Time Imaging of Stopping Distribution• Initial Progress towards LET Measurement

All this with 6 weeks of beam time (1.2 x 1012 pbars)

January 19, 2010

Recent Publications• 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’; submitted to European Physical Journal D (2009)

• Niels Bassler, Ioannis Kantemiris, Julia Engelke, Michael Holzscheiter, Jørgen B. Petersen, ‘Comparison of Optimized Single and Multifield Irradiation Plans of Antiproton, Proton and Carbon Ion Beams’, submitted to Radiotherapy and Oncology (2009)

• Bassler, N., Holzscheiter, M.H., Petersen, J.B., ‘Neutron Fluence in Antiproton Radiotherapy, Measurements and Simulations', submitted to Physics in Medicine and Biology (2009)

• Kantemiris, I., Angelopoulos, A., Bassler, N., Giokaris, N., Holzscheiter, M., Karaiskos, P., Kalogeropoulos, T.E., ‘Real-time imaging for dose evaluation during antiproton irradiation’, Physics in Medicine and Biology, in print (2009)

• Kovacevic, S., Bassler, N., Hartley, O., Vranjes, S., Garaj-Vrhovac, V., Holzscheiter, M., ‘V-79 Chinese Hamster Cells irradiated with antiprotons, a study of peripheral damage due to medium and long range components of the annihilation radiation’, Int. J. of Rad. Biology 85: pp. 1148-1156 (2009)

• Fahimian, B.P., DeMarco, J.J., Keyes, R., Bassler, N., Iwamoto, K.S., Zankl, M., Holzscheiter, M.H., ‘Antiproton radiotherapy: peripheral dose from secondary neutrons’, Hyperfine Interaction 194: pp. 313-318 (2009)

• Bassler, N., Holzscheiter, M. 2009, ‘Calculated LET Spectrum from Antiproton Beams Stopping in Water’, Acta Oncologica 48: pp. 223-226 (2009)

January 19, 2010

Summary and Outlook

Summary and OutlookFuture Work• Increase precision of RBE determination

Better biological protocolsHigher data density to stabilize fits

• Continue DNA damage studies to assess risk of secondary primary malignancies (SPM’s)

• Detailed dose planning studies on specific cancers• Develop 2D LET measuring system• Complete real-time imaging pilot experiment• Transfer technology between HIT and AD-4

- Protons, Carbon ions, AntiprotonsJanuary 19, 2010

Beam Time Request1 week of 126 MeV (500 MeV/c) antiprotons• Survival measurements on V-79 cell lines• Study of DNA damage using H2AX and MN• Liquid ionization chamber measurements

January 19, 2010

“Standard” 5 MeV (100 MeV/c) antiprotons• Commissioning of modified beam line • Real time imaging• Beam monitor development• Response of detectors and Gafchromic film

to annihilation events