AD-4/ACE Status Report CERN, 21 th November 2006 Niels Bassler

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

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

3. PROTON THERAPY

4. PROTON THERAPY x-rays protons

5. PROTON THERAPY x-rays protons

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

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

8. ANTIPROTON THERAPY ?

9. ANTIPROTONS The idea ... (FLUKA Calculation)

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

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

12. 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.. 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)

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

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

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 0.5-1 mm are plated on Petri-dishes, and the colonies are counted.

16. CERN Results (CERN data from 2003)

17. 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...) Relative Biological Efficiency (RBE) Usually one would then measure the RBE (in the plateau and the peak) for antiprotons.. for iso-effect

18. 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...) Relative Biological Efficiency (RBE) Usually one would then measure the RBE (in the plateau and the peak) for antiprotons.. for iso-effect ?

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

20. 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...

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... Findings were recently published in “Radiotherapy and Oncology” Radiother Oncol (2006), doi:10.1016/j.radonc.2006.09.012

22. 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.

23. IN ANNIHILATION VERTEX: Thermoluminescent Detectors (TLD) Alanine GAFChromic Film 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 PERIPHERAL REGION: Thermoluminescent Detectors (TLD) Neutron Bubble Detectors

24. ANTIPROTON DOSIMETRY TLDs IN ANNIHILATION VERTEX: • Thermoluminescent Detectors (TLD) • Alanine • GAFChromic Film 7LiF and 6LiF Alanine IN PERIPHERAL REGION: Thermoluminescent Detectors (TLD) Neutron Bubble Detectors GAFChromic Film Bubble detectors

25. 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! Alanine TLD – entire signal

26. 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.

27. Comparison of Calculations and Measurements New results from CERN - 2003 & 2004 run.

28. Comparison of Calculations and Measurements New results from CERN - 2003 & 2004 run.

29. 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 - 2003 & 2004 run.

30. 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.

31. OCTOBER 2006 EXPERIMENTSStatus

32. October 2006 – New Experiments Main feature this year: Increased energy - 125 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

33. 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

34. Ionization chamber measurement in water target. • Earlier thought to be impossible • Boag's two-voltage method applied to correct for general recombination. (eff. corr 1-0.8 !)

35. Oct. 2006 - Results of Ionization Chamber Measurements • Data presented here are relative. Calibration of chamber scheduled within next weeks.

36. Oct. 2006 - 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.

37. Oct. 2006 - Results of Ionizationchamber Measurements • FLUKA 2006.3 • Success! Very satisfying result!

38. Oct. 2006 - 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)

39. Oct. 2006 - GAFChromic Film Irradiation • Films are not analyzed yet. • An alternative dosimeter with different LET response. • Additional dose verification, (and on site beam verification)

40. Oct. 2006 – Biology BEDR/RBE Measurements • Analysis in progress, as dose delivered is not yet known. PRISTINE SOBP • (MAASTRO, University of Maastricht)

41. Oct. 2006 – 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.)

42. 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. Summary

43. 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.