GSI Helmholtzzentrum fr Schwerionenforschung Gmb H Particle Therapy

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GSI Helmholtzzentrum für Schwerionenforschung Gmb. H Particle Therapy at GSI C. Graeff GSI Biophysics

GSI Helmholtzzentrum für Schwerionenforschung Gmb. H Particle Therapy at GSI C. Graeff GSI Biophysics GSI Helmholtzzentrum für Schwerionenforschung Gmb. H

GSI Helmholtz Center for Heavy Ion Research Budget: ~100 M€ Employees: 1350 incl. scientists

GSI Helmholtz Center for Heavy Ion Research Budget: ~100 M€ Employees: 1350 incl. scientists & engineers: 750 Visiting scientists: 1000 Darmstadt Large facility equipment: accelerators and experiments 1998 – 2008: pilot project of scanned ion therapy GSI Helmholtzzentrum für Schwerionenforschung Gmb. H Cave M 2

Towards FAIR • Research continues „FAIR Phase 0“ • regular beam from GSI FAIR

Towards FAIR • Research continues „FAIR Phase 0“ • regular beam from GSI FAIR April 2014 GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 2018 on (SIS 18) Future Beams: Intensity: primary HI 100 -fold secondary RIB 10000 -fold Species: Z = -1 – 92 (anti-protons to uranium) Energies: ions up to 35 - 45 Ge. V/u antiprotons 0 -15 Ge. V/c Precision: full beam cooling

Physics research questions § Basic components of matter Ø Why don‘t we observe free

Physics research questions § Basic components of matter Ø Why don‘t we observe free quarks? Ø Why are protons and neutrons much heavier than their components? Ø Which combination of protons and neutrons gives stable nuclei and what are properties of non-stable nuclei? Ø What are basic symmetries existing in nature and which physics laws do they reflect? GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 4

Physics research questions § Evolution of the universe GSI Helmholtzzentrum für Schwerionenforschung Gmb. H

Physics research questions § Evolution of the universe GSI Helmholtzzentrum für Schwerionenforschung Gmb. H Ø What came after the Big Bang? Ø Can we create quark-gluon pasma in heavy ion reactions? Ø Which nuclear reactions are taking place during nuclear fusion? What is the role of non-stable nuclei in fusion? Ø In which state occurs nuclear matter under high temperature and pressure? Ø What is so called dark matter? Ø Why is our universe from matter and not from antimatter? Can we learn more about symmetry breaking in the universe? 5

One example – CBM experiment 30/08/2017 Workshop on Ions. . . GSI Helmholtzzentrum für.

One example – CBM experiment 30/08/2017 Workshop on Ions. . . GSI Helmholtzzentrum für. Chania Schwerionenforschung Gmb. H 6

The Biophysics department 8 subgroups from basic biology to applied medical physics G. Taucher-Scholz

The Biophysics department 8 subgroups from basic biology to applied medical physics G. Taucher-Scholz (DNA repair) M. Krämer (physical modeling) S. Ritter (chromosome aberrations) C. Graeff (medical physics) C. Fournier (tissue effects) U. Weber (radiation physics) M. Scholz (biological modeling) Department lead currently vacant (until 2015: M. Durante) Interim joint directors: M. Scholz & C. Kausch GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 7

Relative dose 1. 2 Tumor 1. 0 0. 8 Normal tissue Durante & Loeffler,

Relative dose 1. 2 Tumor 1. 0 0. 8 Normal tissue Durante & Loeffler, 0. 6 Nat Rev Clin Oncol 2010 0. 4 Potential advantages of heavy ions 0. 2 0. 0 Depth (mm) Energy high low LET low high Dose low high RBE 1 >1 OER 3 <3 Cell-cycle dependence high low Fractionation dependence high low Angiogenesis Increased Decreased Cell migration Increased Decreased GSI Helmholtzzentrum für Schwerionenforschung Gmb. H • High tumor dose, normal tissue sparing • Effective for radioresistant tumors • Effective against hypoxic tumor cells • Increased lethality in the target because cells in radioresistant (S) phase are sensitized • Fractionation spares normal tissue more than tumor • Reduced angiogenesis and metastatization Tumor therapy with scanned carbon ion beams 28. 04. 2014 8

Tumor therapy at GSI – Cave M § 1997 – 2008: 440 patients treated,

Tumor therapy at GSI – Cave M § 1997 – 2008: 440 patients treated, mainly chordoma & chondrosarcoma of the skull § Project partners: § GSI, Radiooncology Clinic and DKFZ in Heidelberg, Helmholtz Center Dresden/Rossendorf (former FZR) § Succeeded in 2009 by Heidelberg Ion Beam Therapy Center (HIT) GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 9

Therapy developed at GSI § Accelerator control § 255 energies, 7 foci, 15 intensities

Therapy developed at GSI § Accelerator control § 255 energies, 7 foci, 15 intensities – different in each spill § Beam monitoring § Precision dose application: PPIC and MWPC still in use today § Positron emission tomography: beam range § Beam scanning § First clinical use of full 3 D active energy scanning at GSI § Radiobiology & biological modeling § local effect model (LEM I - IV) § Treatment planning software (TRi. P) GSI Helmholtzzentrum für Schwerionenforschung Gmb. H

Haberer et al. 1993 Rasterscanning GSI Helmholtzzentrum für Schwerionenforschung Gmb. H

Haberer et al. 1993 Rasterscanning GSI Helmholtzzentrum für Schwerionenforschung Gmb. H

Scanned beam examples / CR-39 stack [M. Krämer, U. Weber, GSI and Phys. Med.

Scanned beam examples / CR-39 stack [M. Krämer, U. Weber, GSI and Phys. Med. Biol. 2000] GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 12

The treatment plan - example [M. Krämer, U. Weber, GSI and Phys. Med. Biol.

The treatment plan - example [M. Krämer, U. Weber, GSI and Phys. Med. Biol. 2000] GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 13

The Local Effect Model § Current version: LEM IV § Slightly different modeling approach

The Local Effect Model § Current version: LEM IV § Slightly different modeling approach § Supports multiple particles § Proton RBE! § LEM I in clinical use in Siemens Syngo TPS § Heidelberg, Marburg, Pavia, Shanghai § LEM IV licensed to Ray. Search § Will be used at Med. Austron § Main investigator: Michael Scholz GSI Helmholtzzentrum für Schwerionenforschung Gmb. H

Relative Biological Effectiveness RBE [Krämer et al. and Weyrather et al. , GSI] §

Relative Biological Effectiveness RBE [Krämer et al. and Weyrather et al. , GSI] § Linear Energy Transfer ~ stopping power § Modeling required to determine RBE! GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 15

Local Dose [Gy] Basis of the local effect model Tracks Cell nucleus Local Dose

Local Dose [Gy] Basis of the local effect model Tracks Cell nucleus Local Dose [Gy] Photons x 10000 Carbon ions, local GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 16

Local Effect Model LEM Basic Assumption: Increased effectiveness of particle radiation can be described

Local Effect Model LEM Basic Assumption: Increased effectiveness of particle radiation can be described by a combination of the photon dose response and microscopic dose distribution Local Effect (Photons) = Local Effect (Ions) + RBE ! LEM: Transfer of low-LET experience to high-LET GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 17

RBE weighted Dose [Gy] Depth Dependence of RBE GSI Helmholtzzentrum für Schwerionenforschung Gmb. H

RBE weighted Dose [Gy] Depth Dependence of RBE GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 18

GSI Helmholtzzentrum für Schwerionenforschung Gmb. H Positron Emission Tomography Collaboration under lead of Forschungszentrum

GSI Helmholtzzentrum für Schwerionenforschung Gmb. H Positron Emission Tomography Collaboration under lead of Forschungszentrum Dresden-Rossendorf (Wolfgang Enghardt) Starting with re-unification funds in the 90 ies GSI Helmholtzzentrum für Schwerionenforschung Gmb. H

Range uncertainties • (Mostly) controllable for regions with defined bone structure: ~ 1 mm

Range uncertainties • (Mostly) controllable for regions with defined bone structure: ~ 1 mm in head & neck dose 12 C photons range [S. O. Grözinger, GSI] • Much more difficult in chest / abdomen: deformable tissue, breathing & heart beat GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 20

Bragg curve – fragment contribution GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 21

Bragg curve – fragment contribution GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 21

Loss of initial particles • Some projectile fragments are positron emitting isotopes, e. g.

Loss of initial particles • Some projectile fragments are positron emitting isotopes, e. g. 11 C and 10 C (half-lifes: 20 min and 20 sec) • Can be used for Positron Emission Tomography (PET) [E. Haettner, MSc-Thesis] GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 22

PET-control of treatment projectile target [Enghardt et al. Rossendorf] GSI Helmholtzzentrum für Schwerionenforschung Gmb.

PET-control of treatment projectile target [Enghardt et al. Rossendorf] GSI Helmholtzzentrum für Schwerionenforschung Gmb. H Tumor therapy with scanned carbon ion beams 28. 04. 2014 23

Dose verification with PET • 3 D reconstruction by back projection • Positron emitter

Dose verification with PET • 3 D reconstruction by back projection • Positron emitter distribution neither proportional nor equivalent to the dose distribution • Comparison with expected positron emitter distribution Treatment plan [Enghardt et al. Rossendorf] GSI Helmholtzzentrum für Schwerionenforschung Gmb. H Predicted b+activity Measured b+activity 24

Clinical outcome of the pilot project 100 Local control (%) Photons Protons + Photons

Clinical outcome of the pilot project 100 Local control (%) Photons Protons + Photons Carbon Ions overall 10 y-local control: 88% 0 0 50 100 150 200 Time from irradiation (month) Chondrosarcoma Chordoma Schulz-Ertner et al. , IJROBP 2007 Uhl et al. , Cancer 2014 GSI Helmholtzzentrum für Schwerionenforschung Gmb. H 25

Future research topics § FAIR-specific § Space irradiation (C. Schuy, Tuesday) § Particle imaging

Future research topics § FAIR-specific § Space irradiation (C. Schuy, Tuesday) § Particle imaging / theranostics (M. Schanz, Wednesday) § Tissue-level effects / adverse events § Radio-Immunology § Licensed for human stem cells § Radiotoxicity in embryonal development § Radiotoxicity for neuronal / cardiac tissue § Different ion species: He, O § Effect-based optimization: Kill painting § Moving targets (C. Graeff, Wednesday) GSI Helmholtzzentrum für Schwerionenforschung Gmb. H