1. Clinical aspects of carbon ion RT Daniela Schulz-Ertner

2. Particle therapy

3. Lateral scattering Protons Carbon ions Depth 5 cm [LBL data]

4. Dose distribution in nanometer scale Entrance Channel At start of Bragg peak At Bragg peak

5. Definition of RBE

6. Calculations for different sensitivities [M. Scholz, GSI]

7. Which Tumors Are Best For Carbon? CarbonProtons/photons Carbon Sensitive Normal Tissues Resistant Tumors

8. Potential indications for carbon ion RT  Chordoma / low grade chondrosarcoma  Malignant salivary gland tumors  Malignant melanoma of the paranasal sinus  Soft tissue sarcomas and bone tumors  Lung cancer  Liver tumors  Prostate carcinoma

9. Potential advantages of carbon ion RT  precision  reduced integral dose  modification of the biological effectiveness „High-LET“ effect, less pronounced OER Clinical benefit ?

10. Availability of carbon ion RT NIRS, Chiba / Japan Hyogo Ion Beam Medical Center / Japan GSI, Darmstadt / Germany

11. GSI Darmstadt Availability for clinical applications 3 beam time blocks / year 20 days

12. Rasterscan-Technique + - Isoenergetic levels Irradiated volume

13. Passive beam application - constant modulation depth and intensity throughout the field RBE as depth dependent factor [Tsuji 1998] Active beam application (raster scanning) - Adaption of modulation depth at each point - Optimization of intensity at each scan spot RBE calculation at each voxel

14. Principle of the Local-Effect-Model (LEM) Input parameters: radial dose distribution size of cell nucleus x-ray sensitivity (  /  ratio) [Scholz 1996]

15. Therapy parameters at GSI  Immobilization  intensity-controlled raster scanning with pulsed energy variation  3D treatment planning (CT+MRI)  VIRTUOS  TRiP  daily x-ray controls (comparison with DRR)  PET (beam verification)

16. Online verification using PET Stereotactic target point localization

18. Carbon ion radiotherapy at GSI n=264, 1998-2005 Chordoma Chondrosarcoma ACC others Reirradiation 131 58 41 15 19

19. Results of carbon ion RT at NIRS Locally advanced head and neck (phase II, n = 134, 52.8 - 64.0 GyE / 16 Fx / 4 weeks) 2y- LC61% 3y- OS42% [Yamamoto 2005]

20. Combined photon IMRT plus C12 boost total dose 72 CGE (54Gy+18CGE) 60 CGE-Isodose line 39 CGE-Isodose line 54 CGE-Isodose line > 66 CGE a)b)c) [Schulz-Ertner, Cancer 2005]

21. Acute toxicity acceptable late toxicity > CTC Grade 2 < 5% FSRT / IMRT vs FSRT / IMRT+C12 for locally advanced adenoid cystic carcinoma OS LC [Schulz-Ertner, Cancer 2005]

22. Median Dose [Gy] Local tumor control [%] 5J. Conventional RT Dose response relationship for chordomas FSRT, Debus, 2000 Heavy ions, Castro, 1996 Protons, Munzenrider, 1994 Protons, Hug, 1999

23. Prä OP Post OP Carbon ion RT Biologically optimized treatment plan Chondrosarcoma G1/2 Dosis in %

24. Carbon ion RT of skull base chordomas

25. Carbon ion RT for skull base chordomas and chondrosarcomas (phase I/II trial) [Schulz-Ertner, IJROBP 2004]

26. RT of chordomas and chondrosarcomas Author, yearnRT local control Romero, 1993 18conv.RT 17% (CH) Debus, 200045FSRT 50% / 5y (CH) Munzenrider, 1999 519 prot. (+ phot) 73% / 5y (CH) 98% / 5y (CS) Castro, 1994223He 63% / 5y (CH) 78% / 5y (CS) Noel, 200167prot + phot 71% / 3y (CH) 85% / 3y (CS) Schulz-Ertner, 200467C12 74% / 4y (CH)) 87% / 4y (CS)

27. Max. dose variation myelon 14% / mm for C12 8% / mm for photon-IMRT Position #2 [Karger PMB 2003] Phantom measurements C12 #2 #1 REF IMRT REF #1 #2

28. Carbon ion RT of inoperable soft tissue sarcomas [Kamada, JCO 2004] Local control

29. [Miyamato et al. 2003] 5y-overall survival42% 5y-cause-specific survival60% radiation pneumonitis °III3/81 Stage I NSCLC (phase I/II, inoperable PT) 57.6 - 95.4 GyE, 18 Fx, 6 weeks, n = 47, 72 GyE, 9 Fx, 3 weeks, n = 34

30. Results of carbon ion RT at NIRS Hepatocellular carcinoma (Protocol liver-2, phase I/II) n = 82 2y-local control83% 3y-overall survival45% cause of death mostly related to progression of associated liver cirrhosis

31. [Pollack 2002, MD Anderson] Dose escalation for localized prostate cancer

32. [Zelefsky 2001, Memorial Sloan Kettering]

33. Dose-response curve for PC [Hanks 2002, Fox Chase]

34. Rationale for carbon ion RT in locally advanced prostate cancer  /ß = low (1.5 – 3 Gy) hypofractionation ? [Fowler 2003]

35. Particle therapy for localized prostate cancer severe toxicity RT DosenGIGU5J-NED MDACCConv. RT <67 Gy50054% (4y) 67-77Gy49514.8%8.5%71% (4y) >77 Gy13277% (4y) MSKCCIMRT 81.0-86.47724.5%15%86% (3y,IR) 92% (3y,LR) late 1.5% °II81% (3y,HR) LLUMCProtons 75CGE12551% (≥III) 1% (≥III) 48% (HR) NIRSCarbon 66.0GyE1701% (II)6% (II)79% (HR)

37. Influence of organ motion on carbon ion RT  Variance for 95% + 90%-coverage / CTV 3.6% (SD 3.7) + 2.8% (SD 2.8)  Variance for the clinically relevant Dmin 6.2 Gy /GTV, 12.5 Gy /CTV  Variance of the rectal volume > 70 Gy <3cm 3 (Kupelian 2002: rectal volume > 70 Gy <15cm 3 ) [Nikoghosyan 2004]

38. Phase I/II trial Combined photon IMRT + carbon ion boost for locally advanced prostate cancer Photon IMRT 60 Gy / median CTV2 (prostate + seminal vesicles+5mm + individual safety margin) + Carbon ion RT 18 GyE (6 Fx) CTV1 / prostate + individual safety margin

39. Photon IMRT and C12 IMRT C12

40. Carbon ion RT trials at GSI 2003200420052006 Skull base CH+CS ACC Phase I/II spinal/ sacral CH + CS Phase I/II Prostate 30 / year routine 10 / year routine completed 15 / year

41. Heavy Ion Therapy (HIT) in Heidelberg

43. Conclusions  Randomized trials proving the superiority of carbon ion RT in comparison to photon IMRT and protons are lacking, but several combined facilities are planned to be built in Europe and will allow phase III trials in the future  Integration of carbon ion RT into interdisciplinary treatment concepts necessary  First results of clinical phase I and II trials performed at NIRS and GSI support the assumption that carbon ions provide an enhanced biological effectiveness in adenoid cystic carcinomas, H/N melanomas, lung and liver tumors, large soft tissue sarcomas, chordomas / chondrosarcomas and prostate cancer  radiobiologic research will enable better exploitation of the advantages of carbon ion RT in future trials