1. Wolfgang Enghardt OncoRay – Center for Radiation Research in Oncology Technische Universität Dresden, Germany and Forschungszentrum Dresden-Rossendorf, Dresden, Germany Institute of Radiation Physics 1st International Conference on Frontiers in Diagnostic Technologies Frascati (Roma), Italy November, 27, 2009 Diagnostic in Hadron Therapy

2. Outline 1. Diagnostic imaging for radiotherapy 2. Image guided radiotherapy 3. Image based in-vivo dosimetry 4. Particle therapy positron emission tomography 5. In-beam single photon tomography

3. - within normal tissue: selective decrease of the radiation sensitivity (molecular targeting) the dose and the biological effectiveness of the radiation CFSP = TCP × (1 - NTCP) CFSP:Complication free survival probability TCP:Tumour control probability NTCP:Normal tissue complication probability H. Holthusen, 1936: - within the tumour: selective increase of the radiation sensitivity (molecular targeting) the biological effectiveness of the radiation TCP NTCP 1 NTCP 2 Chose such that the tumour will be destroyed the surrounding normal tissue will be saved 1. Diagnostic imaging for radiotherapy The challenge in radiotherapy

4. 1. Diagnostic imaging for radiotherapy Treatment course Fractionated therapeutic irradiation 1) Diagnostic CT imaging 2) Dose prescription, Treatment planning 3)

5. 1. Diagnostic imaging for radiotherapy Increased soft tissue contrast: NMR tomography Courtesy: G. Wolf, OncoRay Dresden Native X-ray CT, soft tissue window Where is the tumour? Tumour bearing rat, transaxial sections Where is the borderline between tumour and normal tissue? T2-weighted MRT

6. 1. Diagnostic imaging for radiotherapy Functional or molecular imaging – PET/CT Metastases of a prostate carcinoma Courtesy: N. Abolmaali, OncoRay Dresden Where is the tumor? X-ray CT PET: 11 C-Acetate Where is the bone? Image fusion

7. 18 F-FDG 1. Diagnostic imaging for radiotherapy Tumour heterogeneity 18 F-MISO O2O2 O2O2  OER (S = 10 %)  2.7 (In-vitro data) Mouth base carcinoma: PET/CT Courtesy: N. Abolmaali, OncoRay Dresden Basis for dose painting: intensity modulated radiotherapy (IMRT), IMXT, IMPT Glucose uptake Hypoxia

8. 1. Diagnostic imaging for radiotherapy Adaptive radiotherapy CT, PET, GTV = CT+PET, PTV = GTV + SM (1 cm) Aim: - Tumor dose escalation up to 80 Gy - Normal tissue doses: Before treatment After dose delivery of 50 Gy: Tumour volume reduction: 49.2 % Potential for irradiation field shrinking PET CT C. Gillham et al. Radiother. Oncol. 88 (2008) 335

9. 2. Image guided radiotherapy Interfractional movement M. Van Herk et al., Netherlands Cancer Institute, Amsterdam, NL Prostate carcinoma Position influenced by the filling state of the bladder and the rectum Movie from daily 3D CT

10. 2. Image guided radiotherapy Intrafractional movement Bronchial carcinoma Position influenced by the breathing motion 4D CT F. Pönisch et al., OncoRay Dresden

11. 2. Image guided radiotherapy Technology at photon/electron beams (Dresden) e - -Linac MV cone beam CT In-room CT on rails kV X-ray position control IR movement tracking

12. 3. Image based in-vivo dosimetry Dose delivery particularities in ion therapy (I)  = 1.0 T 1.0 0  = 1.0 T 1.0 Ions Photons Penetration depth / cm D / D max Effect of density changes in the target volume Similar effects for mispositioning or organ movement

13. 3. Image based in-vivo dosimetry Dose delivery particularities in ion therapy (II) The dose distribution deposited by ions is extremely sensitive to the ion range in vivo The accuracy of the ion range is influenced by (1)Systematic errors in the physical beam model used for treatment planning: R = R(HU) (2) Random errors like - mispositioning - patient- or organ movement - density changes within the irradiated volume - treatment mistakes and accidents Desirable: A procedure for the verification - of the irradiation field position - of the particle range - simultaneous with the therapeutic irradiation and, in particular a procedure for the quantification of the dose distribution - in-situ - in-vivo - in real time.

14. Integrable to therapy units Ions (3D) Non invasive Real time Dose localization In vivo Tomography Highly penetrable signal, proportional to dose Separation of the signal from the therapeutic irradiation , X, n Signal with: well defined energy spatial correlation time correlation time delay Detectors of: - high granularity - high efficiency - compact High detection efficiency 3. Image based in-vivo dosimetry Technological requirements Dose quantification High spatial resolution

15. 3. Image based in-vivo dosimetry The physical dilemma Dose deposition: electronic stopping of ions, i.e. atomic processes Origin of highly penetrable signals: nuclear processes Nucleons and clusters Projectile Target Projectile fragment Target fragment Fireball Prompt  -rays Radioactive nuclides Depth in water / cm 1H1H 4 He 12 C 16 O 20 Ne

16. 4. Particle Therapy Positron Emission Tomography Physical advantages Integrable to therapy units Ions (3D) Non invasive Real time Dose localization In vivo Tomography Highly penetrable signal, proportional to dose Separation of the signal from the therapeutic irradiation , X, n Signal with: well defined energy spatial correlation time correlation time delay Detectors of: - high granularity - high efficiency - compact High detection efficiency Dose quantification High spatial resolution 11 C 11 B + e + + e T 1/2 180 deg  t = 0 E  = 511 keV

17. W. Enghardt et al.: Phys. Med. Biol. 37 (1992) 2127; J. Pawelke et al.: IEEE T. Nucl. Sci. 44 (1997) 1492; K. Parodi et al.: IEEE T. Nucl. Sci. 52 (2005) 778; F. Fiedler et. al.: IEEE T. Nucl. Sci., 53 (2006) 2252; F. Sommerer et al.: Phys. Med. Biol. 54 (2009) 3979; M. Priegnitz et al.: Phys. Med. Biol. 53 (2008) 4443 Peripheral nucleus-nucleus-collisions, nuclear reactions ( A Z, xp,yn), Target fragments 12 C: E = 212 AMeV Target: PMMA 15 O, 11 C, 13 N... 11 C, 10 C Projectile fragments Penetration depth / mm Arbitrary units 16 O: E = 250 AMeV Target: PMMA 15 O, 11 C, 13 N... 15 O, 14 O, 13 N, 11 C … Therapy beam 1H1H 3 He 7 Li 12 C 16 ONuclear medicine Activity density / Bq cm -3 Gy -1 6600530030601600103010 4 – 10 5 Bq cm -3 Z  6 Target fragments Z < 6 1 H: E = 110 MeV Target: PMMA 15 O, 11 C, 13 N... 3 He: E = 130 AMeV Target: PMMA 15 O, 11 C, 13 N... Arbitrary units Penetration depth / mm 7 Li: E = 129 AMeV Target: PMMA 4. Particle Therapy Positron Emission Tomography The physical basis of PT-PET: Autoactivation

18. Principle: production of projectile fragments and separation in flight (HIMAC) E. Urakabe et al.: Jpn. J. Appl. Phys. 40 (2001) 2540 M. Kanazawa et al.: Nucl. Phys. A701 (2002) 244c Stable primary projectiles I = I 0, v = v 0 Target, Be Dipole magnet: separation: ( A/Z ) Dipole magnet: separation: v Projectile fragments + primary projectiles, v = const. Aperture Degrader:  E  Z 2 Clean beam of fragments I ≈ I 0 /1000 12 C, 430 AMeV 11 C, 340 AMeV J. Pawelke et al.: Phys. Med. Biol. 41 (1996) 279 Range / mm FRS at GSI: 20 Ne, 500 AMeV 19 Ne, 406 AMeV 4. Particle Therapy Positron Emission Tomography The physical basis of PT-PET: Radioactive beams

19. J. Pawelke et al.: Phys. Med. Biol. 41 (1996) 279, W. Enghardt et al.: Nucl. Instr. Meth. A525 (2004) 284 12 C   In-beam PET: 12 C-therapy at GSI Darmstadt, Germany 4. Particle Therapy Positron Emission Tomography The instrumentation of PT-PET (I)

20. Off-beam PET: 1 H-therapy at MGH Boston, USA K. Parodi et al.: Int. J. Radiat. Oncol. Biol. Phys. 68 (2007) 920 4. Particle Therapy Positron Emission Tomography The instrumentation of PT-PET (II)

21. T. Nishio et al.: Med. Phys. 33 (2006) 4190 In-beam PET at a rotating beam delivery: 1 H-therapy at the National Cancer Center, Kashiwa, Japan Beam ON-LINE PET system 4. Particle Therapy Positron Emission Tomography The instrumentation of PT-PET (III)

22. 0.66 Gy 0.37 Gy PET PET/CT 4. Particle Therapy PET In-beam, in-room, off-line G. Shakirin: Thesis, TU Dresden, 2009, G. Shakirin et al.: IEEE NSS/MIC 2010, Conference Records

23. 4. Particle Therapy Positron Emission Tomography The clinical workflow  Treatment plan: dose-distribution  + -activity: prediction  + -activity: measurement W. Enghardt et al.: Strahlenther. Onkol. 175/II (1999) 33; F. Pönisch et al.: Phys. Med. Biol. 48 (2003) 2419, Phys. Med. Biol. 49 (2004) 5217; F. Fiedler et al.: Phys. Med. Biol. (submitted) Ion-electron interaction Ion-nucleus interaction Monte Carlo: from the projectiles to the detection of annihilation  -rays Chordoma, 0.5 Gy, 6 min  Range verification,  x = 6 mm, sensitivity = (93 ± 4) %, specifity = (96 ± 3) %

24. Feasibility to solve the inverse problem: A(r) – spatial distribution of activity A(r) = T D(r)D(r) – spatial distribution of dose T – transition matrix K. Parodi, T. Bortfeld: Phys. Med. Biol. 51 (2006) 1991 Dose  + -activity K. Parodi et al.: IJROBP 68 (2007) 920 D < 0.9 D max D > 0.9 D max T 1/2 /s = 74.3 – 0.2 f T 1/2 /s = 86.3 – 0.6 f F. Fiedler et al.: Acta Oncol. 47 (2008) 1077 Double head Closed ring Longitudinal Transaxial P. Crespo et al.: Phys. Med. Biol. 51 (2006) 2143 Solution: Local dose deviation estimation by interactive CT-manipulation and subsequent dose recalculation W. Enghardt et al.: Radiother. Oncol. 73 (2004) S96 Limited angle artefacts (in-beam PET) Quantification of metabolic washout rate of  + -radioactivity impossible - individual - tissue dependent - dose dependent - fraction dependent - disturbed by the tumour 4. Particle Therapy Positron Emission Tomography Limitations of in-beam PET

25. D + TOF A dTOF- reconstruction, parameter  (FWHM) 500 ps 200 ps 100 ps P. Crespo et al., Phys. Med. Biol. 52 (2007) 6795 4. Particle Therapy Positron Emission Tomography Direct TOF-PET: Removing limited angle artifacts

26. State-of-the-art technology (scintillators): Single detector pairs:  150 ps Integrated Systems:   400 ps C.C.M. Kyba et al. 2008 IEEE NSS MIC Conference Record, M10-34 LaPET LaBr 3 Scanner, UPenn M. Moszynski et al., IEEE TNS 53 (2006) 2484 4. Particle Therapy Positron Emission Tomography Time resolution of PET systems

27. Proton beam E p =170 MeV Target: water cylinder r =15 cm, l = 50 cm Detector sphere p Balance of promptly emitted particles outside the target: Incident protons: 1.0 (~10 10 )  -rays:0.3 (3·10 9 ) Neutrons:0.09 (9·10 8 ) Protons:0.001 (1·10 7 )  -particles:2 · 10 -5 (2·10 5 ) GEANT 4  n 5. In-Beam Single Photon Tomography Prompt reaction products

28. 5. In-Beam Single Photon Tomography Monte Carlo predictions:  -ray spectra E p =140 MeV on water    = 10 3 – 10 4 cm 2 · s -1 0 5 10 15 E  /MeV 10 0 10 -2 10 -4 10 -6 10 -8 100 Counts/(MeV p sr) -1 GEANT4

29. 0 25 50 75 100 125 Neutrons cm -2 5. In-Beam Single Photon Tomography Monte Carlo predictions:  -ray and neutron spatial distributions  cm -1 0 50 100 150 200 250 Photons cm -2 Requirement: Neutron blind, high spatial resolution  -camera of wide energy acceptance

30. 5. In-Beam Single Photon Tomography First experimental results GANIL: 13 C - 74 AMeV on PMMA GSI: 12 C - 292 AMeV on water E. Testa et al. Appl. Phys. Lett. 93 (2008) 093506 M. Bajard et al. GSI Scientific Report 2008 1 cm slit Plastic scintillator

31. 11 1‘1‘ 11 11 11 2‘2‘ 22 22 22 22 Absorption detector Coincidence  -ray source Scatterer and e - -detector S. Chelikani et al.: Phys. Med. Biol. 49 (2004) 1387 Sensitivity: Kinematics of incoherent scattering: Problems: - Continuous  -ray spectra - E  unknown -  ‘ must be completely absorped 5. In-Beam Single Photon Tomography Detectors for in-beam SPECT: Compton cameras

32. 5. In-Beam Single Photon Tomography Detectors for in-beam SPECT: Compton cameras Courtesy: D. Dauvergne, ETOILE, Lyon

33. 5. In-Beam Single Photon Tomography A real technical challenge Integrable to therapy units Ions (3D) Non invasive Real time Dose localization In vivo Tomography Highly penetrable signal, proportional to dose Separation of the signal from the therapeutic irradiation , X, n Signal with: well defined energy spatial correlation time correlation time delay Detectors of: - high granularity - high efficiency - compact High detection efficiency Dose quantification High spatial resolution = 0  ENVISION European NoVel Imaging Systems for ION therapy

34. Acknowledgment

35.  -ray source 4. In-beam single particle tomography (WP3) Detectors for in-beam SPECT: Compton cameras Scatterer and e - -detectors E1E1 11 22 E2E2 E3E3 Compton some J.D. Kurfess et al., 5th Compton Symposium, Portsmouth, New Hampshire, AIP Conference Proceedings, 1999 - Efficiency: 25 – 50 % for E 1 > 1 MeV - No absorption necessary - No high Z absorber required

36. Treatment plan Simulation of irradiation Irradiation Spatial distributions of the relevant quantity Simulation of measurement Measurement Tomographic reconstruction Reconstructed spatial distributions Prediction Observer comparison, dose calculations Measurement Imaging Analysis No critical deviation, next fraction Critical deviation Corrections: - New CT - Modified TP - Medication Next fraction 3. Positron Emission Tomography The data processing

37. 0 1 T Time S(t)S(t) Accelerator: Synchrotron d  60 m Particle beam: pulsed T  5 s,  ≤ 2 s   PET data, list mode: {K 1, K 2, S}(t) Irradiation- time course: {E, I, d}(t) 3. Positron Emission Tomography The instrumentation (in-beam PET)

38. Treatment plan: dose distribution  + -activity: prediction  + -activity: measurement 4. Particle Therapy Positron Emission Tomography Limited angle artefacts for in-beam PET

39.  N/  t / (s) -1 250 200 150 100 50 0 200 400 600 800 Decay time / s 1 patient (skull base chordoma), 2 opposing portals, DAQ up to 20 min after irradiation of the right (first) portal, 13 of 20 fractions (averaged) Dose Activity: 0…50 s after irrad. Activity: 550…800 s after irrad. 4. Particle Therapy Positron Emission Tomography Metabolic influence to PT-PET

40. State-of-the-art technology (RPC): Intrinsic time resolution:  50 ps 3. Time-of-flight in-beam PET (WP2) Time resolution of PET systems (II) Y. Sun et al. 2008 IEEE NSS MIC, Conference Record, N03-6 A. Blanco et al., Nucl. Instr. Meth. 53 (2006) 2484