AD-4 Status Report 2010

AD-4 Status Report 2010Biological Effects of Antiprotons

Are Antiprotons a Candidate for Cancer Therapy?

Aarhus University HospitalUniversity of AarhusUniversity of Athens

Queen’s University BelfastCERN, Geneva

Hôpital Universitaire de GeneveGerman Cancer Research Center, Heidelberg

Universita d’Insubria, ComoMax Planck Institute for Nuclear Physics, Heidelberg

University of Montenegro, PodgoricaUniversity of New Mexico, Albuquerque

University of UmeåUniversity of Texas

32 Scientists from 13 Institutions

Dose and tumor control are limited due to organs at risk.

Dose (arb. Gy)

Pro

bab

ility

(%

)

Tumor control

Therapeutic gain

Therapeuticwindow

Complications

Complications

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Rationale for Conformal Radiotherapy

Physical Advantage of Antiprotons

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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), and 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!

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ANALYSIS:

Study cell survival in peak (tumor), plateau (skin), and along the entire beam path. Compare the results to protons (and carbon ions)

INGREDIENTS:

V-79 Chinese Hamster cells embedded in gelatin

Antiproton beam from AD (126 MeV)

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

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V79Developed by Ford and Yerganian in 1958 from lung tissue of a young male Chinese Hamster (Cricetulus griseus)

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Beam

The Gel-Tube Method

Plateau

Peak

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The Gel-Tube Method

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Radiation dose (Gy)

0 2 4 6 8 10

Surviving fraction0.001

0.01

0.1

1

Biological Analysis Method

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Radiation dose (Gy)

0 2 4 6 8 10

Surviving fraction0.001

0.01

0.1

1RBE0.1 1.56

SF0.1

3.31 Gy

SF0.1

5.17 Gy

Relative Biological Efficiency (RBE)

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Cell Survival vs. Dose for 2010 Data

RBEpeak/plateau = 1.52

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4 Years of Running – 4 Depth Dose Distributions

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0 20 40 60 80 100 1200.00

0.20

0.40

0.60

0.80

1.00

1.20

Depth Dose Distributions for 2007 and 2010 Beam Time

DDD 2007DDD 2010

Depth in Gelatin [mm]

Peak

nor

mal

ized

Dose

Two issues: Shift of DDD due to additional beam monitorDifferent shape of SOBP

Combining different years

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Combining different years

0 20 40 60 80 100 1200.00

0.20

0.40

0.60

0.80

1.00

1.20Depth Dose Distribution for 2010 corrected for additional Material

DDD 2007DDD 2010

Depth in Gelatin [mm]

Peak

Nor

mal

ized

Dos

e

Correction applied for insertion of Mimotera Detector

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00 20 40 60 80 100 1200.75

1

1.25

1.5

1.75

2

2.25

RBEpl 2007 & 2010

2010 Data shifted by 4.8 mm

2007 2010

Average

Depth in Gelatin [mm]

RBE

refe

renc

ed to

Ent

ranc

e Ch

anne

l

Combined RBEplateau for 2007 and 2010

Preliminary

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Problems with 2011 Data Set

4 wells seeded with identical number of cells – only two show colonies!

• Physical Dose Calculations requires exact Knowledge of Beam Parameters

• Changes in FLUKA code necessitate new benchmark measurements and new calculations for all years using identical FLUKA version

• Biological Variability necessitates multiple Independent Experiments under Identical Conditions

==> We definitley need more beam time!

RBE Analysis for Antiprotons

January 17, 2012

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 17, 2012

DNA Damage and Repair AssaysThere 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

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Micro-Nuclei Studies

Micro-nuclei produced by annihilating antiprotons are substantially larger and more persistent than those produced

by x-rays or antiprotons in-flight

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Effects of Secondary Particle Dose

Summary and Outlook

Achievements 2011• Biological measurements on clonogenic survival

failed for unknown reason• Started combined analysis of Biological Effect of

Antiprotons for preliminary dose planning studies• DNA damage assays for studies of late effects

achieved higher resolution• 2012 will be “last chance” to significantly improve

statistics on measurement of RBE for antiprotons

January 17, 2012

Summary and OutlookSTILL TO DO IN 2012

• Add two more independent data sets (identical conditions) to improve RBE results

• Perform low LET reference measurements• Benchmark FLUKA code against measured depth dose

distributions.• Recalculate DDD’s for all years with identical code• Combine all years for final result to publish

January 17, 2012

Beam Time Request2 weeks of 126 MeV (500 MeV/c) antiprotons

Week 25 and last week of run time• Survival measurements on V-79 cell lines:

Complete data set on RBEImprove error analysisAchieve publishable result

• Benchmarking Studies for FLUKA code:Provide additional data to FLUKA team to modify code for correct description of antiproton interaction at low energies

• IF there is any beam left after this:Absolute dosimetry with Alanine, Liquid Ionization Chamber studies, DNA damage, etc.

January 17, 2012

Recent Publications• Stefan Sellner, Carsten P. Welsch, Michael Holzscheiter; ‘Real-time imaging of

antiprotons stopping in biological targets - Novel uses of solid state detectors’; Radiation Measurements 46 (2011) 1770 - 1772

• R. Boll, M. Caccia, C.P. Welsch, M.H. Holzscheiter; ‘Using Monolithic Active Pixel Sensors for fast monitoring of therapeutic hadron beams’; Radiation Measurements 46 (2011) 1971 - 1973

• J.N. Kavanagh, F.J. Currell, D.J. Timson, M.H. Holzscheiter, N. Bassler, R. Herrmann, G. Schettino; ‘Experimental setup and first measurements of DNA damage induced along and around an antiproton beam’; European Physical Journal D 60 (2010) 209 - 214

• 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 95 (2010) 87 - 93

• Bassler, N., Holzscheiter, M.H., Petersen, J.B., ‘Neutron Fluence in Antiproton Radiotherapy, Measurements and Simulations', Acta Oncologica 49 (2010) 1149 – 1159

Summary and Outlook

January 17, 2012