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Phase II Study of Proton Radiation Therapy for Spine and Paraspinal Sarcomas

Phase II Study of Proton Radiation Therapy for Spine and Paraspinal Sarcomas. Thomas F. DeLaney,  Norbert J. Liebsch,  Ira J. Spiro,  Patricia L. McManus,  Judith  Adams,  Susan  Dean,  Francis J. Hornicek,  Francis X. Pedlow,  Andrew L. Rosenberg,  G. Petur Nielsen, 

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Phase II Study of Proton Radiation Therapy for Spine and Paraspinal Sarcomas

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  1. Phase II Study of Proton Radiation Therapy for Spine and Paraspinal Sarcomas Thomas F. DeLaney,  Norbert J. Liebsch,  Ira J. Spiro,  Patricia L. McManus,  Judith  Adams,  Susan  Dean,  Francis J. Hornicek,  Francis X. Pedlow,  Andrew L. Rosenberg,  G. Petur Nielsen,  David C. Harmon,  Sam S. Yoon,  Kevin A. Raskin,  Herman D. Suit

  2. Sarcomas of the Spine • Low rates of control with standard therapy • Surgical margins are often positive because of proximity of critical normal tissues • Radiotherapy doses need to be > 66 Gy • Difficult to deliver with spinal cord dose constraint of ~ 50 Gy • Chordoma (Sacrum) • 44% crude local failure rate (Mayo Clinic) • Chondrosarcoma (Spine/Sacrum) • 42% crude local failure rate (Göteborg, Sweden) • Osteosarcoma • 15/22 (68%) local failure (Ozaki, 2002) • Contrast with extremity where local failures < 10%

  3. Sarcomas of the Spine • Hug et al. (Harvard Cyclotron Laboratory) • Photon/proton XRT +/- resection 1980-1992 • 47 pts: osteo-/chondrogenic axial skeletal tumors • XRT: Post-op (23) , Pre/post-op (17), XRT only (7) • Group I: Chordoma/Chondrosarcoma n=20 • Mean 73.9 CGE 5 Year LC 53%/100% • Group II: Osteosarcoma n=15 • Mean 69.8 CGE 5 Year LC 59% • Group III: Giant cell tumor, osteo or chondroblastoma n=12 • Mean 61.8 CGE5 Year LC 83% • Trend to improved LC: primary, > 77 Gy, less residual

  4. Spine and Paraspinal Sarcoma • Spine/Paraspinal Sarcoma (PI T. DeLaney MD) • Surgery + IORT ( Dura Plaque) + Photon/Proton • IRB-approved protocol • Surgery: Maximal debulking/spine stabilization • IORT: 90Y dural plaque: 10 Gy • Photon/Proton Radiotherapy • 70.2 CGE (Microscopic residual)* • 77.4 CGE (Gross residual disease)* * Doses modified for concurrent chemotherapy, diabetes, connective tissue diseases, radioresponsive histologies

  5. Ideal Dose Distribution

  6. L1 Angiosarcoma Proton IMRT ASTRO 2003

  7. Paravertebral Epithelioid SarcomaIntensity Modulated Protons (IMPT) vs. Intensity Modulated Photons (IMRT) (7 field) IMPT IMXT

  8. Spine/Paraspinal Sarcoma: Clinical Trial • Radiation Therapy • CTV1 (clinical target volume) • Tissues suspected of microscopic involvement • Doses: 50.4 CGE at 1.8 Gy per fraction • Could be given with photons • Majority of pts received ~30.6 Gy with photons (conformal or IMRT) • Treated pre-operatively when possible to doses of: • 19.8 Gy : Sacrum 45-50.4 Gy: Thoracolumbar spine • Reduces risk of tumor seeding into wound • Dose selection based upon risk of wound healing delay • CTV dose reduced to 46.8 Gy with IDDM/autoimmune disease

  9. Spine/Paraspinal Sarcoma: Clinical Trial • Radiation Therapy • CTV (clinical target volume) • Controlled information on extent of CTV not available • CTV based upon the patterns of failure in surgical and radiation therapy series • Generally included the entire involved vertebral body and at least hemi-sacral segment in the CTV • Areas of extra-osseous extension into soft tissue are included with 1 cm margin or to fascial barrier • Scar coverage for patients receiving post-op XRT dependent upon histology, grade, length of scar

  10. Spine/Paraspinal Sarcoma: Clinical Trial • Radiation Therapy • GTV (gross tumor volume) • CTV2: Encompasses original gross tumor • Boosted to dose of 70.2 CGE at 1.8 CGE q.d. with protons • Giant cell tumor, Ewing’s sarcoma : 61.2 Gy • CTV3: Residual gross disease after surgery • Boosted to dose of 77.4 CGE at 1.8 CGE q.d. with protons • If IDDM/autoimmune disease or concurrent chemotherapy (i.e. osteosarcoma), doses reduced by 8%: total 70.2-72.0 CGE • Chemotherapy • Adriamycin not delivered concurrently

  11. Spine/Paraspinal Sarcoma: CT myelogram for Radiation Planning T6 spine/paraspinal Chondrosarcoma CT myelogram for lesions above the conus to outline spinal cord

  12. Spine/Paraspinal Sarcoma: Treatment Position LPO Proton Field Thoracic Chondrosarcoma

  13. Spine/Paraspinal Sarcoma: Treatment Planning S1 Chondrosarcoma Treatment Plan

  14. Spine/Paraspinal Sarcoma: Set-Up Verification Set-up Radiograph with Digitized Set-up Points, Actual (red) and Desired (blue) Isocenter Axes Sacral Chondrosarcoma

  15. Spine/Paraspinal Sarcoma: Treatment Planning • Normal tissue constraints • Spinal cord • Surface: 63 CGE Center: 54 CGE (for length up to 5 cm) • Cauda equina • Limit dose to contralateral nerves when possible • Rectum • Use omental flap to displace rectum for sacral chordomas • Small bowel • 50.4 CGE • Skin • Avoid full dose on skin overlying sacrum

  16. Spine/Paraspinal Sarcoma: Treatment Planning • Beam Selection • Protons not stopped on the spinal cord • Concern about end of range uncertainty • RBE variation at end of proton range • Patch fields contour dose around spinal cord

  17. Thoracic Chondrosarcoma Treatment Plan (Protons) 60 year old diabetic female with T9 Chondrosarcoma Radiated after laminectomy 72 CGE (IMRT photons 45 Gy protons 27 CGE)

  18. 90Y Plaque Irradiation Plaque on Dura

  19. Results • Plaques • Comparative depth doses • 192Ir 90Y • 2 mm 80% 27% • 4 mm (cord surface) 60% 8% • 8 mm (cord center) 50% 0%

  20. Exposed Gafchromic Film Surface Exposure %Depth Dose Exposure

  21. Spine and Paraspinal Sarcoma • Accrual target 50 patients • Statistics • Anticipated local failure with lower dose photons estimated to be 50% with spine chordomas at 5 years • 80% power to detect decrease to 30% local failure rate

  22. Spine and Paraspinal Sarcoma • Accrual 50 Patients 12/97-3/2005 • Chordoma 28 Chondrosarcoma 14 • Liposarcomas 2 Angiosarcoma 1 • Ewing’s Sarcoma 1 Giant cell tumor 1 • Malignant schwannoma 1 Osteosarcoma 1 • Spindle and round cell 1 • Thoracic 12 Lumbar 12 Sacrum 26 • Primary 37 Locally recurrent 13 • Extent of surgery • Grossly resected 25 • Subtotally excised 12 • Biopsy only 13 • All but 1 patient completed Rx (social reasons) • Dose delivery within 3% of protocol target in all patients

  23. Spine and Paraspinal Sarcoma • Results • Median follow-up: 27 months • Local Recurrence: 6 at 8-32 months after start of XRT • 2 also with distant metastases • 2 chordomas, 4 chondrosarcomas • 3/13 patients treated for recurrent tumor vs. 3/27 for primary tumor • Distant Metastases: 3 isolated at 11-35 m after start of XRT • LR, DM, and tumor-associated deaths were all in pts with gross residual disease except 1 pt with dedifferentiated chondrosarcoma with tumor cut through at initial surgery • Survival • 3 died of progressive tumor (2 chondrosarcoma, 1 malig schwannoma) • 2 died unrelated causes (cardiac, oral cancer) • 1 lost to follow-up

  24. Sacral Chordoma T1 post-gadolinium sagittal MRI Pre-treatment S3-4 chordoma 77.4 CGE (photons 30.6 Gy protons 46.8 CGE)

  25. Sacral Chordoma Treatment Plan S3-4 chordoma 77.4 CGE (photons 30.6 Gy protons 46.8 CGE)

  26. Sacral Chordoma Treatment Plan S3-4 chordoma 77.4 CGE (photons 30.6 Gy protons 46.8 CGE)

  27. Sacral Chordoma T1 post-gadolinium sagittal MRI S3-4 chordoma 77.4 CGE (photons 30.6 Gy protons 46.8 CGE) No evidence of progressive disease at 19 months

  28. Unresectable SacralOsteosarcoma: Axial CT scan 19 year old with S1 Osteosarcoma After 12 weeks of chemotherapy Concurrent chemoradiation starting week 16 70.2 CGE (photons 18 Gy protons 52.2 CGE)

  29. Unresectable SacralOsteosarcoma: Treatment Plan (Axial) 19 year old with S1 Osteosarcoma After 12 weeks of chemotherapy Concurrent chemoradiation starting week 16 70.2 CGE (photons 18 Gy protons 52.2 CGE)

  30. Unresectable SacralOsteosarcoma: Axial CT scan 19 year old with S1 Osteosarcoma 29 months after treatment Chemotherapy + 70.2 CGE (photons 18 Gy protons 52.2 CGE) No evidence of progressive disease

  31. Multiply (x4) recurrent G2 chondrosarcoma T4

  32. Multiply recurrent G2chondrosarcoma T4

  33. Multiply recurrent G2 chondrosarcoma T4

  34. Multiply recurrent G2chondrosarcoma T4 Local recurrence 40 months after Surgery, plaque, XRT

  35. Multiply (x6) recurrent G2 chondrosarcoma T spine

  36. Dedifferentiated chondrosarcoma L spine

  37. Multiply recurrent chondrosarcoma T spine

  38. Multiply recurrent chondrosarcoma T spine

  39. Spine and Paraspinal Sarcoma • Acute Complications • > Grade 3 • 1 painful sacral stress fracture without late sequelae. • Late Complications • > Grade 3 • 1 sacral neuropathy: Large, unresected sacral chordoma ( 77.4 CGE) LE weakness, stress urinary incontinence, poor rectal tone at 5.5 years • 1 erectile dysfunction: 65 y.o. unresected sacral chordoma (77.4 CGE) 4 yrs • Grade 2 • 1 erectile dysfunction: 46 y.o. recurrent T3-5 chondrosarcoma and cord compressions (77.4 CGE) at 2 years; responsive to sildenafil • One late sacral stress fracture after fall, 3 months after XRT and subtotal intralesional excision/MMA packing; managed with nail; chronic pain

  40. Spine and Paraspinal Sarcoma • Conclusions • High dose photon/proton XRT can be delivered • Morbidity to date appears acceptable. • Encouraged to date by the treatment results with these challenging tumors • Await further follow-up • Prefer to radiate at time of initial presentation • Potential concern about late sacral nerve toxicity in patients receiving 77.4 Gy

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