AD-4/ACE Status Report CERN, 21 th November 2006 Niels Bassler Dept. Clinical Experimental Oncology, Aarhus University Hospital and Deutsches Krebsforschungszenrum, Heidelberg

2 Radiotherapy The Quest: Hit the tumour, save the surrounding tissue!

3 PROTON THERAPY

4 x-rays protons

5 PROTON THERAPY x-rays protons

6 IMRT vs. IMPT Treatment Plans (Weber et al.) x-rays protons

7 IMRT vs. IMPT vs. IMAT Treatment Plans (Weber et al.) x-rays protons

8 ANTIPROTON THERAPY ?

9 ANTIPROTONS (FLUKA Calculation) The idea...

10 Antiproton Annihilation Energy from annihilation : 2x m p ~ 1.88 GeV Most of the energy is carried away by pions and gammas. Recoiling nuclei do the local damage, “only” about 30 MeV pions Gamma-rays neutrons Nuclei (fragments)

11 GAFChromic Film Irradiation Antiprotons (3 different energies) CERN – 2003 Protons (3 different energies) ASTRID, Århus, DK.

12 Radiobiology Dose is not everything! There is also Radiobiology: High-LET radiation do more cell damage for the same physical dose -> higher Relative Biological Efficiency (RBE) Due to the high LET behaviour in the antiproton peak it is not sufficient to consider physical dose alone, when doing the treatment plan. RBE must be modeled in the treatment plan as well, since it depends on particle type, energy, tissue type etc..

13 Therefore the Radiobiology of the Antiproton beam was investigated at CERN:

14 The AD4/ACE Experiment at CERN SCINTILLATOR (1 of 2) CCD CAMERA BEAM CURRENT MONITOR WATER PHANTOM TARGET BEAM DEGRADER

15 AD4/ACE - The Test Tube Chinese V79 Hamster Cells suspended in gelatine solution. Cooled to a few °C to stop cell repairing. After irradiation, slices of mm are plated on Petri-dishes, and the colonies are counted.

16 Proton data from TRIUMF Proton beam was degraded Relative Biological Efficiency (RBE)

17 CERN Results (CERN data from 2003)

18 Relative Biological Efficiency (RBE) Usually one would then measure the RBE (in the plateau and the peak) for antiprotons.. BUT : it is not possible to determine the RBE if the physical dose is unknown ! Antiprotons have a mixed particle field, difficult to measure. (Ionization chambers were thought to be unusable...) for iso-effect

19 Relative Biological Efficiency (RBE) Usually one would then measure the RBE (in the plateau and the peak) for antiprotons.. BUT : it is not possible to determine the RBE if the physical dose is unknown ! Antiprotons have a mixed particle field, difficult to measure. (Ionization chambers were thought to be unusable...) ? for iso-effect

20 Biological Effective Dose Ratio (BEDR) Biology Physics ( F : physical dose ratio between peak and plateau. ) BEDR : New parameter which can be measured. BEDR describes dose ratio for peak/plateau for iso- effect. (Any number proportional to the fluence) (CERN data from 2003)

21 Biological Effective Dose Ratio (BEDR) BEDR for antiprotons : ~ 9.8 BEDR for protons (TRIUMF) : ~ 2.5 => antiprotons may be 9.8/2.5 ~ 4 times more effective in reducing the the damage to normal tissue for the same peak dose, relative to a similar degraded proton beam...

22 Biological Effective Dose Ratio (BEDR) BEDR for antiprotons : ~ 9.8 BEDR for protons (TRIUMF) : ~ 2.5 => antiprotons may be 9.8/2.5 ~ 4 times more effective in reducing the the damage to normal tissue for the same peak dose, relative to a similar degraded proton beam... Findings were recently published in “Radiotherapy and Oncology” Radiother Oncol (2006), doi: /j.radonc

23 ANTIPROTON DOSIMETRY BEDR is nice, but sooner or later the RBE must be measured. Therefore dosimetry in the annihilation peak is inevitable. Dosimetry in the plateau is easier, since antiprotons behave as protons at high velocities.

24 ANTIPROTON DOSIMETRY Purpose: 1) Estimate dose in peak region 2) If possible derive information about particle spectrum in annihilation peak 3) Estimate peripheral damage (neutrons) IN ANNIHILATION VERTEX: Thermoluminescent Detectors (TLD) Alanine GAFChromic Film IN PERIPHERAL REGION: Thermoluminescent Detectors (TLD) Neutron Bubble Detectors

25 ANTIPROTON DOSIMETRY IN ANNIHILATION VERTEX: Thermoluminescent Detectors (TLD) Alanine GAFChromic Film IN PERIPHERAL REGION: Thermoluminescent Detectors (TLD) Neutron Bubble Detectors TLDs 7 LiF and 6 LiF Alanine GAFChromi c Film Bubble detector s

26 Dosimetry TLDs and Alanine respond highly non-linear to high-LET radiation. Response is depending on particle energy, charge, mass, fluence. And even experimental findings of efficiencies are ambiguous! TLD – entire signal Alanine

27 Dosimetry – Detector Efficiency Models Assuming no significant track interaction: (low fluence and large linear region for gamma dose-response curve) A track structure model (by Hansen et al.) were used for Alanine calculations. For TLD ECLaT (based on the Local Effect Model) was applied. If significant track interaction exists, the mixed radiation field simulated by SHIELD- HIT were directly applied in ECLaT (new version MECLaT was developed) (high fluence and/or early onset of non-linear effect for gamma dose-response curve)

28 Dosimetry – Detector Efficiency Models A track structure model (by Hansen et al.) were used for estimating Alanine response. For estimating the TLD response in the antiproton beam the ECLaT model (based on the Local Effect Model) was applied. Track structure models can possibly be applied to GAFChromic Films as well. The Local Effect Model (LEM) is being used by GSI and DKFZ to predict RBEs of various cell lines in mixed particle field from Carbon ion beams with some success.

29 Comparison of Calculations and Measurements New results from CERN & 2004 run.

30 Comparison of Calculations and Measurements New results from CERN & 2004 run.

31 Peripheral Results With TLDs the contribution from gammas, protons and pions were measured, as well as thermal neutrons. Results (here shown per 10^7 pbars) indicate similar dose contribution as seen with proton therapy using a passive degrader. New results from CERN & 2004 run.

32 The central question we now want to have answered is: What clinical results could be expected from antiproton therapy based on these observations? Currently, the only way to give a proper answer to this question is to perform planning studies for several real cases with Antiprotons and compare with that of X-rays, protons and carbon ions. For implementing antiprotons in a treatment planning system (TPS), exact knowledge of the dose and biology of the antiproton beam is vital. This is happening at the DKFZ – the “TRiP98” TPS is going to be modified. Unlike conventional proton treatment planning software, TRiP includes a biology model (LEM). Simultaneously, GEANT with the biological module is investigated.

33 OCTOBER 2006 EXPERIMENTS Status

34 October 2006 – New Experiments Main feature this year: Increased energy MeV instead of 46 MeV as in 2003/2004. => larger penetration depth (~10 cm instead of ~2 cm) 1) more precise study of the effects from inflight annihilation (!) 2) better seperation of peak/plateau 3) more energy straggling => natural increased width of peak 4) possibility of generating a 1 cm SOBP

35 October 2006 – New Experiments DOSIMETRY primarily addressing the in-flight annihilation question Ionization chamber measurements Two Alanine stacks irradiated GAFChromic Film Irradiation (HS + EBT) BIOLOGY Survival Curves (Clonogenic assay) >New< : Genetic expression experiment

36 Ionization chamber measurement in water target. Earlier thought to be impossible Boag's two-voltage method applied to correct for general recombination. (eff. corr !)

37 Oct Results of Ionization Chamber Measurements Data presented here are relative. Calibration of chamber scheduled within next weeks.

38 Oct Results of Ionizationchamber Measurements Comparison with FLUKA and SHIELD-HIT MC code. SHIELD-HIT v. 2.2 Slight overestimation of peak dose. Presumably underestimation of inflight annihilation.

39 Oct Results of Ionizationchamber Measurements FLUKA Success! Very satisfying result!

40 Oct Alanine Irradiation Alternative dosimeter, in case of ionization chamber failed. Test of response model and particle spectrum from particle annihilation. Dose -> Response calculation not yet performed. (will use Johnny model)

41 Oct GAFChromic Film Irradiation Films are not analyzed yet. An alternative dosimeter with different LET response. Additional dose verification, (and on site beam verification)

42 Oct – Biology BEDR/RBE Measurements Analysis in progress, as dose delivered is not yet known. PRISTINE SOBP (MAASTRO, University of Maastricht)

43 Oct – Biology Gene Expression Experiment Genetic expression study of a human cell line (FaDu) SOBP used (clinical relevance) Slices from the Bragg-peak and a slice from the plateau have been prepared. Qualititive experiment (understand why is RBE higher) (Dept. of Clinical Oncology at the University Hospital in Aarhus.)

44 Summary Antiprotons seem ~4 times more effective delivering the dose in the peak region than protons or in other words: normal tissue dose could be reduced ~4 times for the same target dose. FLUKA was benchmarked and will most likely be the preferred choice for Monte Carlo simulation of Antiproton annihilation. This dataset will be used for implementing antiprotons in treatment planning system, and benchmarking it.

45 Outlook RBEs can very soon be extracted, based on experimentally verified MC simulations. Heavy-ion treatment planning system TRiP from DKFZ/GSI will be modified to support antiprotons. Further investigation of the far peripheral damage – (stochastic effects.) Further investigation of the biological effect in the immediate surrounding of the beam (i.e. “the tail”). We will then be able to evaluate the clinical potential of antiproton therapy.