Antiproton Cancer Therapy AD- -4/ACE 4/ACE Antiproton Cancer - - PowerPoint PPT Presentation

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Antiproton Cancer Therapy AD- -4/ACE 4/ACE Antiproton Cancer - - PowerPoint PPT Presentation

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Antiproton Cancer Therapy AD- -4/ACE 4/ACE Antiproton Cancer Therapy AD Antiproton Cancer Therapy Science or Fiction? Antiproton Cancer Therapy Science or Fiction? The Biological Effectiveness of Antiproton Annihilation Nzhde Agazaryan 1 ,

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SLIDE 1

Michael H. Holzscheiter, AD-4 1 SPSC, November 15, 2005

Antiproton Cancer Therapy Antiproton Cancer Therapy Science or Fiction? Science or Fiction? AD AD-

  • 4/ACE

4/ACE Antiproton Cancer Therapy Antiproton Cancer Therapy

The Biological Effectiveness of Antiproton Annihilation

Nzhde Agazaryan1, Niels Bassler2, Gerd Beyer3, John DeMarco1, Michael Doser4, Oliver Hartley3, Michael Holzscheiter5, Kei Iwamoto1, Sandra Kovacevic6, Helge Knudsen2, Rolf Landua4, Carl Maggiore5, Bill McBride1, Søren Pape Møller2, Jorgen Petersen7, Vesna Popovic6, Danijela Scepanovic6, Tim Solberg8, Ulrik Uggerhøj2, Sanja Vranjes9, Rod Withers1, Brad Wouters10

1 UCLA Medical School, 2 University of Aarhus, 3 Geneva University Hospital 4 CERN, 5 PBar Labs, LLC, 6 University of Montenegro, 7 Aarhus University Hospital 8 University of Nebraska Medical Center, 9 Vinca Institute, 10University of Maastricht

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SLIDE 2

Michael H. Holzscheiter, AD-4 2 SPSC, November 15, 2005

Antiproton Annihilation in Tissue

Higher Physical dose Enhanced RBE? Real Time Imaging

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SLIDE 3

Michael H. Holzscheiter, AD-4 3 SPSC, November 15, 2005

Antiproton Therapy is based on three claims which need experimental proof:

  • Antiprotons deliver a higher biological dose for

Antiprotons deliver a higher biological dose for equal effect in the entrance channel than protons equal effect in the entrance channel than protons or

  • r

carbon ions carbon ions

  • The damage outside the beam path due to long and

The damage outside the beam path due to long and medium range annihilation products is small. medium range annihilation products is small.

  • Antiprotons offer the possibility of real time imaging

Antiprotons offer the possibility of real time imaging using high energy gammas and pions, even at low using high energy gammas and pions, even at low (pre (pre-

  • therapeutical

therapeutical) beam intensity ) beam intensity

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SLIDE 4

Michael H. Holzscheiter, AD-4 4 SPSC, November 15, 2005

Experimental Set-up

INGREDIENTS: V-79 Chinese Hamster cells embedded in gelatin Antiproton beam from AD (46.7 MeV) METHOD: Irradiate cells for prescribed fluencies to give dose values where survival in the peak is between 0 and 90 % Slice samples, dissolve gel, incubate cells, and look for number of colonies ANALYSIS: Study survival vs. dose in peak and plateau and compare to protons (and carbon ions)

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SLIDE 5

Michael H. Holzscheiter, AD-4 5 SPSC, November 15, 2005

Biological Analysis Technique

  • Irradiate sample tube with

living cells suspended in gel.

  • Slice sample tube in ≤1 mm

slices and determine survival fraction for each slice. Repeat for varying (peak) doses.

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SLIDE 6

Michael H. Holzscheiter, AD-4 6 SPSC, November 15, 2005

Biological Analysis Technique

Dose (arb. units) Calculate “plateau” survival using slices 1 – 4. Determine “peak” survival from slice 8 and 9. Plot “peak” and “plateau” survival vs. relative dose (Plateau dose, particle fluence, etc.) and extract the Biological Effective Dose Ratio BEDR = F • RBEpeak/RBEplateau

(F = ratio of physical dose in peak and plateau region)

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SLIDE 7

Michael H. Holzscheiter, AD-4 7 SPSC, November 15, 2005

Antiproton Experiment - Data

Plateau average (slices 1,2) Peak average (slices 8,8’,9,9’)

2 4 6 8 10 12 14 16 18 20 22 24 0.01 0.1 1

B - 1Gy E - 1Gy C - 2Gy D - 3Gy F - 5Gy J - 25 Gy

Surviving Fraction Depth (mm)

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SLIDE 8

Michael H. Holzscheiter, AD-4 8 SPSC, November 15, 2005

Antiproton - Proton Comparison

SUMMARY of BEDR STUDIES

Antiprotons Protons

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SLIDE 9

Michael H. Holzscheiter, AD-4 9 SPSC, November 15, 2005

Antiproton - Proton Comparison

5 10 15 20 25 30 10

  • 2

10

  • 1

10 BEDR(20%S) =9.5

Plateau Broad peak average Narrow peak average

Surviving Fraction

Particle Fluence (arb. units)

CERN (50 MeV Antiprotons) CERN (50 MeV Antiprotons)

Dose (arb. units)

TRIUMF (50 TRIUMF (50 MeV MeV Protons) Protons)

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SLIDE 10

Michael H. Holzscheiter, AD-4 10 SPSC, November 15, 2005

Summary of Clonogenic Experiments

  • We obtained complete survival curves for 3 and 5

We obtained complete survival curves for 3 and 5 different dose values respectively in two different dose values respectively in two independent experiments and observed good independent experiments and observed good agreement between the experiments. agreement between the experiments.

  • An analysis of the data for the BEDR gives a

An analysis of the data for the BEDR gives a result which is significantly higher than the value result which is significantly higher than the value for protons obtained under nearly identical for protons obtained under nearly identical experimental conditions. experimental conditions.

  • We observe only negligible cell kill outside of the

We observe only negligible cell kill outside of the beam in either the radial or axial (beyond the beam in either the radial or axial (beyond the peak) direction at even the highest dose. peak) direction at even the highest dose.

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SLIDE 11

Michael H. Holzscheiter, AD-4 11 SPSC, November 15, 2005

Evidence of low Peripheral Damage

0.0001 0.001 0.01 0.1 1 10 5 10 15 20 25 30 Depth [mm] Survival 4.6 GY 13.8 GY

2σ 1σ

Sample Tube

Radial

5 10 15 20 25 30 35 40 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Tail Moment Depth in Gelatin [mm]

Comet Assay

5 10 15 20

Depth (mm)

Distal

At the highest dose we can see a small effect outside the Bragg peak up to few mm distance from the direct beam Further work: High central dose: Clonogenic studies. DNA damage: COMET, H2AX Assay.

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SLIDE 12

Michael H. Holzscheiter, AD-4 12 SPSC, November 15, 2005

Comparison to Carbon?

5 10 15 20 25 30 35 5 10 15 20 25 30 Range [m

Using data from Weyrather et al. IJRB 75,1357-1364 (1999) Using SRIM 2003 to calculate dose profile:

Peak Plateau Ratio Dose (dE/dx [eV/A]) 29 4.6 6.3 RBE 3.9 2.3 1.7 BEDR = 10

Peak Plateau

BEDR = F * RBEPeak/RBEPlateau F = Dose Ratio Peak to Plateau

Peak Plateau Ratio Dose (dE/dx [eV/A]) 31 10.2 3.0 RBE 3.9 2.3 1.7 BEDR = 5.1

Direct experimental comparison is needed !

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SLIDE 13

Michael H. Holzscheiter, AD-4 13 SPSC, November 15, 2005

Future Work

  • The BEDR enhancement is significant !!! What

The BEDR enhancement is significant !!! What’ ’s next??? s next???

  • Complete measurement cycle through carbon tests.

Complete measurement cycle through carbon tests.

(Experiment at GSI approved (Experiment at GSI approved – – collaboration with Kraft et al.) collaboration with Kraft et al.)

  • Radiobiological experiments

Radiobiological experiments

(Oxygen Enhancement Ratio/Repair) (Oxygen Enhancement Ratio/Repair)

  • Detailed studies of the peripheral damage.

Detailed studies of the peripheral damage.

( (Clonogenics Clonogenics, COMET, H2 , COMET, H2Α ΑX) X)

  • Increased efforts on

Increased efforts on dosimetry dosimetry (BEDR (BEDR RBE) RBE). .

(Experimental work, Model calculations (Experimental work, Model calculations – – LEM) LEM)

  • Continued development of Monte Carlo capabilities.

Continued development of Monte Carlo capabilities.

(MCNPX, GEANT4, SHIELD (MCNPX, GEANT4, SHIELD-

  • HIT)

HIT)

  • Real time imaging.

Real time imaging.

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SLIDE 14

Michael H. Holzscheiter, AD-4 14 SPSC, November 15, 2005

Radiobiological Measurements

  • The need of direct carbon/antiproton comparison experiments.

The question “How do antiprotons compare to carbon ions, which also show a strong increase in RBE towards the end of range?” has been raised many times.

  • Higher energy irradiation:

Our initial experiments at CERN were limited by the available beam energy of 50 MeV. This resulted in a very shallow penetration depth into the biological target of about 10 mm, taking into account additional material intercepting the beam, and makes the separation of effects extremely difficult if not impossible. Higher beam energy (15 cm penetration) is needed for the most important experiments!

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SLIDE 15

Michael H. Holzscheiter, AD-4 15 SPSC, November 15, 2005

High Energy Beam

At 50 MeV kinetic Energy the effective penetration is only 10 mm. The separation between “Peak” and “Plateau” is less than the range of the high LET annihilation products. A clear separation of high and low LET component is not possible!

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SLIDE 16

Michael H. Holzscheiter, AD-4 16 SPSC, November 15, 2005

Radiobiological Measurements

  • The need of direct carbon/antiproton comparison experiments.

The question “How do antiprotons compare to carbon ions, which also show a strong increase in RBE towards the end of range?” has been raised many times.

  • Higher energy irradiation:

Our initial experiments at CERN were limited by the available beam energy of 50 MeV. This resulted in a very shallow penetration depth into the biological target of about 10 mm, taking into account additional material intercepting the beam, and makes the separation of effects extremely difficult if not impossible. Higher beam energy (15 cm penetration) is needed for the most important experiments!

  • Oxygen Enhancement Ratio (OER)

Hypoxic cells limit the efficacy of current (low LET) radiotherapy. For high LET radiation the OER is much reduced and hypoxia has a smaller consequence to the treatment outcome. When evaluating the potential merit of new radiation treatments, such as carbon or antiprotons, it is important to characterize the dose modifying effect of oxygen.

  • Repair mechanism

For low LET radiation, the vast majority of DNA damage is effectively repaired. This is easily

  • bservable in cells deficient for DNA double-strand break (DSB) repair. However, for high LET

radiation the influence of DNA repair is smaller. The difference in response between repair proficient and repair deficient cells gives an indication of the relative fraction of repairable lesions. To properly assess the advantages of antiprotons we need to clearly separate the high and low LET regions. At 50 MeV the distance peak – plateau is only 5 mm!!

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SLIDE 17

Michael H. Holzscheiter, AD-4 17 SPSC, November 15, 2005

Monte Carlo Calculations

Guidance for Experiments through Dose Calculations

Monte Carlo calculations can determine physical dose distributions. Demonstrated success for protons for both MCNPX and SHIELD-HIT (and for 12C with SHIELD). Unclear situation for antiprotons. Problems with GEANT4. Needs Benchmark!!!

Prediction of Biological Effect (combine MC and LEM) Development of Dosimetry for high LET Beams

Monte Carlo calculations can determine complete spectrum of secondary particles and their energy distributions (in principal). Use as input for Local Effect Model to calculate biological dose (and dosimeter response). Demonstrated with 12C and if successful with antiprotons, biological dose plans can be developed and replace significant fractions of otherwise needed animal testing! Use MC + LEM to predict detector response – also benchmark possibility

Guidance for Imaging Development

MC is standard tool for detector development and study

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SLIDE 18

Michael H. Holzscheiter, AD-4 18 SPSC, November 15, 2005

Energy Deposition Pbars/Carbon/Protons

SHIELD-HIT Transport Code*

calculates physical dose in 2 cm cylinder embedded in a 20 cm diameter water phantom Benchmark against Proton/Carbon experiments (and by comparison to MCNPX and GEANT4).

*)Nikolai Sobolevsky (INR/Karolinska)

Energy deposition by pencil beam in 2 cm Ø cylinder

  • f water embedded in 20 cm Ø water phantom.
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SLIDE 19

Michael H. Holzscheiter, AD-4 19 SPSC, November 15, 2005

MCNPX

Summary Plot 202 MeV Antiprotons in 2cm Diameter Water Target

1.0E-06 1.0E-05 1.0E-04 1.0E-03 1.0E-02 1.0E-01 1.0E+00 1.0E+01 50 100 150 200 250 300 350 400 450 Depth [mm] Dose [MeV/g] Total Dose Neutrons Proton/Antiproton Pions Gammas Kaons Alphas Deuterons Tritons 3He Electrons

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SLIDE 20

Michael H. Holzscheiter, AD-4 20 SPSC, November 15, 2005

MCNPX: Low LET/High LET

Component of high LET(RBE) z z 30 % in peak < < 10 % in plateau Better OER than 12C

(Possible therapeutic gain)

RBE close to 1 in plateau Easier dose planning Possible fractionation gain

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SLIDE 21

Michael H. Holzscheiter, AD-4 21 SPSC, November 15, 2005

MCNPX: Axial Profile and Dose Plan

Bragg Peak is 5 – 6 mm wide !!!!

MCNPX can provide:

Information on Beam Profile

(at 150 MeV Bragg Peak is sufficiently wide for protocol) Peak Dose is 50 x 10-8 cGy/pbar

But we must certify the Calculations against Benchmark Experiments! If Dose Error < 10% BEDR RBE Absolute Dose Values

(needed for planning of irradiations)

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SLIDE 22

Michael H. Holzscheiter, AD-4 22 SPSC, November 15, 2005

Experimental Program 2006/2007

  • I. Biological Measurements (2 Year Program)

Antiprotons (at CERN) Carbon Ions (at GSI)

BEDR at 50 MeV (completed) BEDR for 50 MeV equivalent 12C BEDR for 150 MeV antiprotons Oxygen Enhancement Ratio 150 MeV Repair Efficient/Deficient Cells 150 MeV BEDR for 391 MeV/amu 12C Oxygen Enhancement Ratio 391 MeV/amu Repair Efficient/Deficient Cells 391 MeV/amu (same penetration)

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SLIDE 23

Michael H. Holzscheiter, AD-4 23 SPSC, November 15, 2005

Experimental Program 2006/2007

  • II. Physics Measurements - Antiprotons (at CERN)
  • Beam Development (needs to be done first)

Higher Energy Extraction to clearly separate Effects between Peak and Plateau Regions. AD-Cycle: Inject – Decelerate – Cool to 300 MeV/c and then reaccelerate and immediately extract to DEM line.

  • Dosimetry Tests

Increase data set using TLD’s, Film, and Alanin to be used as Benchmark for MCNPX/SHIELD + LEM Calculations

  • Real Time Imaging Development

Silicon pixel detector (read-out, resolution, etc.) Amorphous X-ray detector (mask, background, etc.) GEANT4 studies

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SLIDE 24

Michael H. Holzscheiter, AD-4 24 SPSC, November 15, 2005

Real Time Imaging

Initial Imaging tests using amorphous silicon detectors with fast read-out

Converter for 30 MeV γ’s worked ok at higher energy!

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SLIDE 25

Michael H. Holzscheiter, AD-4 25 SPSC, November 15, 2005

Beam Time Request 2006

Beam Development

Set up 150 MeV Extraction 96 Spread-out Bragg peak (1x) 24

Dosimetry & Imaging Studies

8

TOTAL Hours 160 Radiobiological Measurements

Clonogenic Survival at 150 MeV (1 of 2) 24 Hypoxic cell irradiation (1 of 2) 16 Repair deficient cells irradiation (1 of 2) 16 Peripheral damage measurements (parasitically)

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SLIDE 26

Michael H. Holzscheiter, AD-4 26 SPSC, November 15, 2005

AD-4 Collaboration

Centre Medicale Universitaire/Hopital Universitaire, 1211 Geneva, Switzerland

  • G. Beyer, O. Hartley, R. Miralbell, C. Pastor, O. Ratib

CERN, PH Department, 1211 Geneva, Switzerland

  • M. Doser, R. Landua

David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, U.S.A.

  • N. Agazaryan, J. J. DeMarco, K. S. Iwamoto, W. H. McBride, H. Rodney Withers

Pbar Labs, LLC, Santa Fe, NM 87501, U.S.A.

  • M. H. Holzscheiter, C. Maggiore
  • Dept. of Rad. Onc., GROW Research Inst., Univ. of Maastricht, The Netherlands
  • B. G. Wouters

University of Aarhus and University Hospital, DK 8000 Aarhus C, Denmark

  • N. Bassler, H. V. Knudsen, S. Pape Møller, J. Petersen, U. I. Uggerhøj

University of Montenegro, Podgorica, Serbia and Montenegro

  • D. Hajdukovic, S. Kovacevic, V. Popovic, D. Scepanovic

University of Nebraska Medical Center, Omaha, NE 68182, U.S.A.

  • T. Solberg, tba

Vinca Institute of Nuclear Sciences, 1101 Belgrade, Serbia and Montenegro

  • S. Vranjes

*) Italic entries are under negotiations