1. Hadron Radiotherapy Pavel Kundrát Institute of Physics, Academy of Sciences of the Czech Republic, Prague Pavel.Kundrat@fzu.cz

2. Outline Introduction Introduction Hadron radiotherapy Hadron radiotherapy Principles Principles Technical requirements Technical requirements Existing centres Existing centres Treatment planning, mathematical modelling Treatment planning, mathematical modelling

3. Introduction Cancer: Cancer: 2 nd major cause of death 2 nd major cause of death A form of cancer is diagnosed to every 3 rd person A form of cancer is diagnosed to every 3 rd person Czech Rep.: 60 000 new tumours/year (10 mil. inhabitants) Czech Rep.: 60 000 new tumours/year (10 mil. inhabitants) Cure rate: 45 – 50% only Cure rate: 45 – 50% only Surgery,, chemotherapy Surgery, radiotherapy, chemotherapy Strategies: Strategies: Early detection, improved diagnostics Early detection, improved diagnostics Improved local treatment Improved systemic treatments Improved systemic treatments

4. Radiotherapy Biological effects of ionizing radiation Biological effects of ionizing radiation Aim: tumour eradication, minimal risk of complications Aim: tumour eradication, minimal risk of complications Inactivate clonogenic tumour cells Inactivate clonogenic tumour cells Spare normal tissues & cells Spare normal tissues & cells Lethal tumour dose Lethal tumour dose Tolerance doses of healthy tissues Tolerance doses of healthy tissues Dose conformity Dose conformity Fractionation Fractionation

5. Conventional radiotherapy Photons, electrons ( 60 Co, linac) Photons, electrons ( 60 Co, linac) Decreasing depth-dose curves Decreasing depth-dose curves Multiple-field irradiation Multiple-field irradiation

6. IMRT: Intensity Modulated RT Non-homogeneous intensity profile Non-homogeneous intensity profile High dose to target volume High dose to target volume Normal tissue burden distributed to a larger area Normal tissue burden distributed to a larger area Dose escalation Dose escalation E. Pedroni (2000)

7. Hadron radiotherapy

8. Protons, ions Protons, ions (60-250 MeV, 100-400 MeV/amu) Bragg peak → excellent conformation Bragg peak → excellent conformation Bragg peak position given by particle energy Bragg peak position given by particle energy Beam modulation Beam modulation Increased biological effectiveness (RBE ion =D x /D ion ) Increased biological effectiveness (RBE ion =D x /D ion ) Diminishing oxygen effect (OER=D hypoxic /D oxic ) Diminishing oxygen effect (OER=D hypoxic /D oxic ) Fractionation Fractionation Online monitoring PET Online monitoring PET

9. PhotonsProtons

10. Beam modulation: Passive spreading

11. Beam modulation: Active scanning

12. Hadron radiotherapy vs. IMRT Photon IMRT Protons – IMPT (active scanning, 4 fields) E.Pedroni, Europhysics News 31, 2000 Target volume: nasopharynx + lymph nodes (yellow) Organs at risk: brainstem, parotid glands (red)

13. Hadrontherapy: Technical requirements Range in tissue Range in tissue Eye tumours2 – 3.5 cm Eye tumours2 – 3.5 cm Head & neck tumours2 – 10 cm Head & neck tumours2 – 10 cm Deep seated tumours2 – 25 cm Deep seated tumours2 – 25 cm Energy Energy Protons220 – 250 MeV Protons220 – 250 MeV Ions up to 400 MeV / amu Ions up to 400 MeV / amu Shift in Bragg peak position (1 – 3 mm) Shift in Bragg peak position (1 – 3 mm) → energy shifts (0.5 – 1 MeV) Field size Field size Dose rate → particle fluence Dose rate → particle fluence Accelerators Accelerators Cyclotron (IBA, Accel) Cyclotron (IBA, Accel) Synchrotron (PIMMS, PRAMES, Optivus, Mitsubishi, Hitachi) Synchrotron (PIMMS, PRAMES, Optivus, Mitsubishi, Hitachi) Fixed beams (horizontal, vertical), gantry Fixed beams (horizontal, vertical), gantry Beam modulation - passive spreading, active scanning Beam modulation - passive spreading, active scanning

14. Hadrontherapy worldwide Nuclear physics centres Berkeley, Harvard (USA), Dubna, Moscow (Russia), PSI (Switzerland), Nice, Orsay (France) → medical facilities Loma Linda (CA, USA) 1991 HIMAC Chiba (Japan) 1994 NCC Kashiwa (Japan) 1998 NPTC Boston (USA) 2001 Wan Jie PTC (China) 2004 RPTC Munich (Germany) 2006 Nuclear physics centres Berkeley, Harvard (USA), Dubna, Moscow (Russia), PSI (Switzerland), Nice, Orsay (France) → medical facilities Loma Linda (CA, USA) 1991 HIMAC Chiba (Japan) 1994 NCC Kashiwa (Japan) 1998 NPTC Boston (USA) 2001 Wan Jie PTC (China) 2004 RPTC Munich (Germany) 2006 Approx. 25 centres + 20 in planning (USA, Europe, Japan) Approx. 25 centres + 20 in planning (USA, Europe, Japan) Almost 50000 patients (protons + ions) Almost 50000 patients (protons + ions) Potential patients: 1000-3000 per year / 10 mil. inhabitants Potential patients: 1000-3000 per year / 10 mil. inhabitants Main indications: head & neck tumours eye tumours NSCLC lung cancer prostate cancer Main indications: head & neck tumours eye tumours NSCLC lung cancer prostate cancer Clinical results: 5 yrs. local control photon vs. hadron RT chordomas 17-50% vs. 73-83% chondrosarcomas 50-60% vs. 90-98% Clinical results: 5 yrs. local control photon vs. hadron RT chordomas 17-50% vs. 73-83% chondrosarcomas 50-60% vs. 90-98% Costs: initial costs 70-120 mil. € (1000 pt/y) about 20 000 € / patient approx. 2-3x more expensive than photon RT, about the same as surgery, by far less expensive than chemotherapy Costs: initial costs 70-120 mil. € (1000 pt/y) about 20 000 € / patient approx. 2-3x more expensive than photon RT, about the same as surgery, by far less expensive than chemotherapy Particle Therapy Co-Operative Group (PTCOG) Particle Therapy Co-Operative Group (PTCOG) http://ptcog.web.psi.ch/ http://ptcog.web.psi.ch/

15. Proton therapy facilities (1) NPTC Boston 2001 NPTC Boston 2001 IBA proton cyclotron, 230 MeV IBA proton cyclotron, 230 MeV Compact design (6m diameter) Compact design (6m diameter) Fixed energy + energy degrader Fixed energy + energy degrader Kashiwa, Japan 1998 Wan Jie PTC, China 2004 MPRI Bloomington, USA 2006 Florida PT Inst, USA 2006 Beijing, China 2007 NCC, Seoul, Korea 2006 Kashiwa, Japan 1998 Wan Jie PTC, China 2004 MPRI Bloomington, USA 2006 Florida PT Inst, USA 2006 Beijing, China 2007 NCC, Seoul, Korea 2006 [NPTC Boston, 2001] [IBA]

16. Proton therapy facilities (2) RPTC Munich RPTC Munich Superconducting cyclotron Accel, 250 MeV protons Superconducting cyclotron Accel, 250 MeV protons 4 gantries (Schär AG), 1 fixed beam 4 gantries (Schär AG), 1 fixed beam Plan: 4000 patients / year Plan: 4000 patients / year Tests & commissioning; operating in 2006? Tests & commissioning; operating in 2006? PSI Villigen – PROSCAN PSI Villigen – PROSCAN Synchrotrons – Loma Linda (>10000 pts since 1991), MD Anderson CC Optivus, Mitsubishi, Hitachi Synchrotrons – Loma Linda (>10000 pts since 1991), MD Anderson CC Optivus, Mitsubishi, Hitachi [Accel/Schär]

17. Ion therapy Rationale: Rationale: Physical selectivity Physical selectivity Increased biological effectiveness, diminishing oxygen effects (→ radioresistant tumours) Increased biological effectiveness, diminishing oxygen effects (→ radioresistant tumours) Online dose monitoring (PET) Online dose monitoring (PET) Hypofractionation Hypofractionation Cyclotrons: ongoing research (IBA 400 MeV/amu superconducting cyclotron) Cyclotrons: ongoing research (IBA 400 MeV/amu superconducting cyclotron) Synchrotrons: PIMMS, HICAT, Siemens, Mitsubishi Synchrotrons: PIMMS, HICAT, Siemens, Mitsubishi Pulsed beam Pulsed beam Variable energy Variable energy Active scanning Active scanning PIMMS: 23 m diameter PIMMS: 23 m diameter Protons 60-250 MeV Protons 60-250 MeV Carbon 120-400 MeV/amu Carbon 120-400 MeV/amu Several projects within the EU Several projects within the EU

18. HICAT Heidelberg Heavy Ion Cancer Therapy Centre Heavy Ion Cancer Therapy Centre p48-220 MeV p48-220 MeV He72-330 MeV/amu C88-430 MeV/amu O102-430 MeV/amu Linac: 5m, 7 MeV/amu Linac: 5m, 7 MeV/amu Synchrotron, 20m diameter Synchrotron, 20m diameter Gantry 20m x 13m diameter (120t), active scanning Gantry 20m x 13m diameter (120t), active scanning Preclinical operation 2006, clinical - 2007 Preclinical operation 2006, clinical - 2007

19. Other p + ion hadrontherapy centres in Europe PIMMS design PIMMS design CNAO Pavia (Italy) 2007 CNAO Pavia (Italy) 2007 ETOILE Lyon (France) ETOILE Lyon (France) MedAustron Wiener Neustadt (Austria) MedAustron Wiener Neustadt (Austria) Karolinska, Stockholm (Sweden) Karolinska, Stockholm (Sweden) Prague? Prague? ENLIGHT network ENLIGHT network

20. ENLIGHT, European Commission, QLG1-CT-2002-01574, 2002-2005 European Network for Light Ion Hadron Therapy, European Commission, QLG1-CT-2002-01574, 2002-2005 ESTRO, CERN, EORTC, GSI Darmstadt, DKFZ Heidelberg, GHIP Heidelberg, TERA, Karolinska Institutet, ETOILE Project, Med-Austron, FZR Rossendorf, Linköping University, Hospital Virgen de la Macarena, Charles University in Prague ESTRO, CERN, EORTC, GSI Darmstadt, DKFZ Heidelberg, GHIP Heidelberg, TERA, Karolinska Institutet, ETOILE Project, Med-Austron, FZR Rossendorf, Linköping University, Hospital Virgen de la Macarena, Charles University in Prague Workpackages: Workpackages: Epidemiology and patient selection Epidemiology and patient selection Design and conduct of clinical trials Design and conduct of clinical trials Preparation, delivery and dosimetry of ion beams Preparation, delivery and dosimetry of ion beams Preparation of Ion Beams Preparation of Ion Beams Dosimetry of Ion Beams Dosimetry of Ion Beams Treatment Planning Treatment Planning Accelerator Technology Accelerator Technology Radiation biology Radiation biology In-situ monitoring with positron emission tomography In-situ monitoring with positron emission tomography Health-Economic Assessment Health-Economic Assessment ENLIGHT++ proposal (2006) ENLIGHT++ proposal (2006)

21. Summary – Hadron therapy Excellent dose conformity Excellent dose conformity Proven clinical benefits in several tumours/locations Proven clinical benefits in several tumours/locations Approx. 1000 – 3000 pts/year/10 mil. inhabitants would benefit from HT Approx. 1000 – 3000 pts/year/10 mil. inhabitants would benefit from HT Ion therapy: radioresistant tumours Ion therapy: radioresistant tumours Costs: initial ~ 70-120 M€, per pt ~ 20 k€ Costs: initial ~ 70-120 M€, per pt ~ 20 k€

22. Biological effects of ionizing radiation: Mechanism and its modelling

23. Motivation Biological effects are not given by deposited dose only Biological effects are not given by deposited dose only Increased biological effectiveness (RBE) of light ions Increased biological effectiveness (RBE) of light ions RBE=D X /D ion depends on Z, E, D,..., cell repair capacity, … RBE=D X /D ion depends on Z, E, D,..., cell repair capacity, … Needs to be integrated into TP systems Needs to be integrated into TP systems Need for detailed biology-oriented models, reflecting the underlying mechanisms Need for detailed biology-oriented models, reflecting the underlying mechanisms DoseBiological effect

24. Radiobiological mechanism Physical phase Physical phase (10 -18 – 10 -10 s) Energy transfer, excitations, ionizations, radical formation Energy transfer, excitations, ionizations, radical formation Chemical phase Chemical phase (10 -10 – 10 -3 s) Diffusion, recombination, chemical reactions, DNA damage (base modification, base loss, cross-link, SSB, DSB, LMDS) Diffusion, recombination, chemical reactions, DNA damage (base modification, base loss, cross-link, SSB, DSB, LMDS) Biological phase Biological phase (seconds – hours, years) Repair processes (BER, HR, NHEJ), cellular response, apoptosis, necrosis; organ, organism Repair processes (BER, HR, NHEJ), cellular response, apoptosis, necrosis; organ, organism

25. Probabilistic two-stage model Kundrát P, Lokajíček M, Hromčíková H (2005) Phys. Med. Biol. 50 1433-1447 Kundrát P (2006) Phys. Med. Biol. (in press), arXiv: physics/0509053 Mono-energetic particles: Mono-energetic particles: Number of primary particles, k: P k (D) = [(hD) k /k!]exp(-hD) h~σ/LET Number of primary particles, k: P k (D) = [(hD) k /k!]exp(-hD) h~σ/LET Transferred energy ε ~ LET Transferred energy ε ~ LET DNA damage induction DNA damage induction Lethal lesions formed by single particles … a „single-particle“ lesions Lethal lesions formed by single particles … a „single-particle“ lesions Sublethal lesions … b Lethal if combined from at least 2 particles „combined“ lesions Sublethal lesions … b Lethal if combined from at least 2 particles „combined“ lesions Repair processes Repair processes Repair success probability … r k Repair success probability … r k Effect of k particles Effect of k particles Cell survival probability s(D) = Σ P k (D) q k Cell survival probability s(D) = Σ P k (D) q k General case: General case: Transferred energy π 1 (ε), π k (ε)= ∫ π 1 (ε’) π k-1 (ε-ε’) dε’ Transferred energy π 1 (ε), π k (ε)= ∫ π 1 (ε’) π k-1 (ε-ε’) dε’ Cell survival s = Σ P k ∫ q k (ε) π k (ε) dε Cell survival s = Σ P k ∫ q k (ε) π k (ε) dε

26. Detailed analysis of the response of different cell lines to carbon irradiation Hromčíková H, Kundrát P, Lokajíček M (2005) 14th Symposium on Microdosimetry, Venezia, Italy; arXiv: physics/0512044 analysis of survival data for CHO-K1 and repair-deficient CHO mutant xrs5 irradiated by carbon ions (2.4 – 266.4 MeV/u, 13.7 – 482.7 keV/μm) equal damage yields, different radiation sensitivities due to different repair capacities (r xrs5 =0) q k =[1-(1-(1-a) k )(1-r a )][1-(1-(1-b 2 ) k(k-1)/2 )(1-r b )]

27. Mechanism of cell inactivation by different ions: damage induction probabilities per single tracks Kundrát P, Lokajíček M, Hromčíková H, Judas L (2005) 14th Symposium on Microdosimetry, Venezia, Italy; arXiv: physics/0512028 Damage probabilities in dependence on LET and effective charge Z eff 2 /β 2 Single-track lesions Combined lesions p■, □0.57–7 MeV5.8 – 37.8 keV/μm 3 He●, ○1.13 – 2.3 MeV/u58.9 – 105.8 keV/μm 12 C ▲, Δ 2.4 – 266.4 MeV/u13.7 – 482.7 keV/μm 16 O ▼,  1.9 – 396 MeV/u18 – 754 keV/μm 20 Ne♦,  8.0 – 395 MeV/u28 – 452 keV/μm

28. Towards biology-oriented treatment planning in hadron radiotherapy Kundrát P (2005) 14th Symposium on Microdosimetry, Venezia, Italy; arXiv: physics/0512028 Bragg peak model Energy loss: SRIM-2003 Energy-loss straggling: effective depth straggling, variance σ[cm] = 0.012 x 0.951 [cm] A -0.5 Attenuation of primary particle fluence Φ due to nuclear reactions Φ = Φ 0 exp(– x / λ) λ - nuclear interaction length, x - depth Fragmentation, scattering: not represented Radiobiological model Effective version, considering unrepaired damage only Damage induction probabilities per track at given LET (single-track lesions - a, two-track lesions - b) Derived from survival data for mono-energetic ions Average damage probability per track along Bragg peak depth Weighting over LET spectrum π i (L) (and different ion species with abundances ρ i ) at given depth a = Σ i ρ i ∫a i (L)π i (L)dL, b = Σ i ρ i ∫b i (L)π i (L)dL Survival after the traversal of k particles q k = (1-a) k [(1-b) k + kb(1-b) k-1 ] Distribution of ion tracks over cell nuclei: Poisson statistics, mean number of primary particles reduced due to nuclear reactions P k = exp(-h) h k /k!, h = σ cell nucleus Φ 0 exp(– x / λ) Survival probability: s = Σ k P k q k Bragg peaks – C, 195 and 270 MeV/u CHO cells – C, 187 MeV/u, 2x10 7 cm -2 CHO cells – C, 264 MeV/u, 2 and 5x10 7 cm -2

29. On the biophysical interpretation of lethal DNA lesions induced by ionizing radiation Kundrát P, Stewart RD (2005) 14th Symposium on Microdosimetry, Venezia, Italy; arXiv: physics/0512030 Numbers of lethal events Derived from survival data of V79 cells irradiated by protons, 0.57–5.01 MeV (LET 7.7 – 37.8 keV/µm) [Belli et al 1998; Folkard et al 1996] Probabilistic two-stage model [Kundrát et al 2005] Monte Carlo estimated yields of different classes of DNA damage and the outcome of excision repair of non-DSB lesions Initial yields of DSBs, SSBs, base damage Enzymatic DSBs through aborted excision repair of SSBs, point mutations through mis-repair of SSBs and base damage Combined MCDS/MCER simulations [Semenenko and Stewart 2004; Semenenko et al 2005; Semenenko and Stewart 2005] Clustered lesions play important role in reproductive cell death Differences in biological effectiveness of radiations of diverse quality correlate with the differences in the yields of complex DSBs Certain subclasses of complex DSBs, e.g. approx. 3 – 5% of DSB 8+, may be intrinsically unrepairable or are often lethally mis-rejoined

30. Summary – Modelling P2S model P2S model Biology-oriented model Biology-oriented model DNA damage & repair DNA damage & repair Systematic description of survival curves → TCP, NTCP models Systematic description of survival curves → TCP, NTCP models Future work Future work Relate damage induction to track structure Relate damage induction to track structure Interpretation of lethal events Interpretation of lethal events TCP, NTCP models TCP, NTCP models Pavel.Kundrat@fzu.cz