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Clinical aspects of carbon ion RT Daniela Schulz-Ertner

Clinical aspects of carbon ion RT Daniela Schulz-Ertner. Particle therapy. Depth. Lateral scattering. Protons. Carbon ions. 5 cm. [LBL data]. Dose distribution in nanometer scale. At Bragg peak. At start of Bragg peak. Entrance Channel. Definition of RBE.

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Clinical aspects of carbon ion RT Daniela Schulz-Ertner

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

  2. Particle therapy

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

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

  5. Definition of RBE

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

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

  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 Irradiated volume + - Isoenergetic levels

  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

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

  18. 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- LC 61% 3y- OS 42% [Yamamoto 2005]

  19. a) b) c) 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 [Schulz-Ertner, Cancer 2005]

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

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

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

  23. Carbon ion RT of skull base chordomas

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

  25. RT of chordomas and chondrosarcomas Author, year n RT local control Romero, 1993 18 conv.RT 17% (CH) Debus, 2000 45 FSRT 50% / 5y (CH) Munzenrider, 1999 519 prot. (+ phot) 73% / 5y (CH) 98% / 5y (CS) Castro, 1994 223 He 63% / 5y (CH) 78% / 5y (CS) Noel, 2001 67 prot + phot 71% / 3y (CH) 85% / 3y (CS) Schulz-Ertner, 2004 67 C12 74% / 4y (CH)) 87% / 4y (CS)

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

  27. 1.0 .8 .6 .4 Survival(n=57) .2 0.0 0 10 20 30 40 50 60 Carbon ion RT of inoperable soft tissue sarcomas Local control [Kamada, JCO 2004]

  28. 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 5y-overall survival 42% 5y-cause-specific survival 60% radiation pneumonitis °III 3/81 [Miyamato et al. 2003]

  29. Results of carbon ion RT at NIRS Hepatocellular carcinoma (Protocol liver-2, phase I/II) n = 82 2y-local control 83% 3y-overall survival 45% cause of death mostly related to progression of associated liver cirrhosis

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

  31. [Zelefsky 2001, Memorial Sloan Kettering]

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

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

  34. Particle therapy for localized prostate cancer severe toxicity RT Dose n GI GU 5J-NED MDACC Conv. RT <67 Gy 500 54% (4y) 67-77Gy 495 14.8% 8.5% 71% (4y) >77 Gy 132 77% (4y) MSKCC IMRT 81.0-86.4 772 4.5% 15% 86% (3y,IR) 92% (3y,LR) late 1.5% °II 81% (3y,HR) LLUMC Protons 75CGE 1255 1% (≥III) 1% (≥III) 48% (HR) NIRS Carbon 66.0GyE 170 1% (II) 6% (II) 79% (HR)

  35. 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 <3cm3 (Kupelian 2002: rectal volume > 70 Gy <15cm3) [Nikoghosyan 2004]

  36. Phase I/II trial Combined photon IMRT + carbon ion boostfor 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

  37. Photon IMRT and C12 IMRT C12

  38. Carbon ion RT trials at GSI 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 2003 2004 2005 2006

  39. Heavy Ion Therapy (HIT) in Heidelberg

  40. 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

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