Phase II Study of Proton Radiation Therapy for

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

Phase II Study of Proton Radiation Therapy for Spine and Paraspinal Sarcomas Thomas F. De. Laney, Norbert J. Liebsch, Ira J. Spiro, Patricia L. Mc. Manus, 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 Harvard Medical School

Sarcomas of the Spine • Low rates of control with standard therapy • Surgical

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% Harvard Medical School

Sarcomas of the Spine • Hug et al. (Harvard Cyclotron Laboratory) – Photon/proton XRT

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 – Mean 73. 9 CGE 5 Year LC 53%/100% • Group II: Osteosarcoma – Mean 69. 8 CGE 5 Year LC n=15 59% • Group III: Giant cell tumor, osteo or chondroblastoma – Mean 61. 8 CGE 5 Year LC n=20 n=12 83% – Trend to improved LC: primary, > 77 Gy, less residual Harvard Medical School

Spine and Paraspinal Sarcoma • Spine/Paraspinal Sarcoma (PI T. De. Laney MD) – Surgery

Spine and Paraspinal Sarcoma • Spine/Paraspinal Sarcoma (PI T. De. Laney MD) – Surgery + IORT ( Dura Plaque) + Photon/Proton • • IRB-approved protocol Surgery: Maximal debulking/spine stabilization 90 Y dural plaque: 10 Gy IORT: 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 Harvard Medical School

Ideal Dose Distribution Harvard Medical School

Ideal Dose Distribution Harvard Medical School

L 1 Angiosarcoma Proton IMRT ASTRO 2003 Harvard Medical School

L 1 Angiosarcoma Proton IMRT ASTRO 2003 Harvard Medical School

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

Paravertebral Epithelioid Sarcoma Intensity Modulated Protons (IMPT) vs. Intensity Modulated Photons (IMRT) (7 field) IMPT IMXT Harvard Medical School

Spine/Paraspinal Sarcoma: Clinical Trial • Radiation Therapy • CTV 1 (clinical target volume) –

Spine/Paraspinal Sarcoma: Clinical Trial • Radiation Therapy • CTV 1 (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 Harvard Medical School

Spine/Paraspinal Sarcoma: Clinical Trial • Radiation Therapy – CTV (clinical target volume) • Controlled

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 Harvard Medical School

Spine/Paraspinal Sarcoma: Clinical Trial • Radiation Therapy • GTV (gross tumor volume) – CTV

Spine/Paraspinal Sarcoma: Clinical Trial • Radiation Therapy • GTV (gross tumor volume) – CTV 2: 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 – CTV 3: 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 Harvard Medical School

Spine/Paraspinal Sarcoma: CT myelogram for Radiation Planning T 6 spine/paraspinal Chondrosarcoma CT myelogram for

Spine/Paraspinal Sarcoma: CT myelogram for Radiation Planning T 6 spine/paraspinal Chondrosarcoma CT myelogram for lesions above the conus to outline spinal cord Harvard Medical School

Spine/Paraspinal Sarcoma: Treatment Position LPO Proton Field Thoracic Chondrosarcoma Harvard Medical School

Spine/Paraspinal Sarcoma: Treatment Position LPO Proton Field Thoracic Chondrosarcoma Harvard Medical School

Spine/Paraspinal Sarcoma: Treatment Planning S 1 Chondrosarcoma Treatment Plan Harvard Medical School

Spine/Paraspinal Sarcoma: Treatment Planning S 1 Chondrosarcoma Treatment Plan Harvard Medical School

Spine/Paraspinal Sarcoma: Set-Up Verification Set-up Radiograph with Digitized Set-up Points, Actual (red) and Desired

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

Spine/Paraspinal Sarcoma: Treatment Planning • Normal tissue constraints • Spinal cord – Surface: 63

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 Harvard Medical School

Spine/Paraspinal Sarcoma: Treatment Planning • Beam Selection – Protons not stopped on the spinal

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 Harvard Medical School

Thoracic Chondrosarcoma Treatment Plan (Protons) 60 year old diabetic female with T 9 Chondrosarcoma

Thoracic Chondrosarcoma Treatment Plan (Protons) 60 year old diabetic female with T 9 Chondrosarcoma Radiated after laminectomy 72 CGE (IMRT photons 45 Gy protons 27 CGE) Harvard Medical School

90 Y Plaque Irradiation Plaque on Dura Harvard Medical School

90 Y Plaque Irradiation Plaque on Dura Harvard Medical School

Results • Plaques Comparative depth doses 192 Ir 90 Y • 2 mm 80%

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

Exposed Gafchromic Film Surface Exposure %Depth Dose Exposure Harvard Medical School

Exposed Gafchromic Film Surface Exposure %Depth Dose Exposure Harvard Medical School

Spine and Paraspinal Sarcoma • Accrual target 50 patients – Statistics • Anticipated local

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 Harvard Medical School

Spine and Paraspinal Sarcoma • Accrual 50 Patients 12/97 -3/2005 – – – Chordoma

Spine and Paraspinal Sarcoma • Accrual 50 Patients 12/97 -3/2005 – – – Chordoma Liposarcomas Ewing’s Sarcoma Malignant schwannoma Spindle and round cell • Thoracic 12 • Primary 37 • Extent of surgery – – – 28 2 1 1 1 Chondrosarcoma Angiosarcoma Giant cell tumor Osteosarcoma Lumbar 12 Sacrum 26 Locally recurrent 13 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 Harvard Medical School 14 1 1 1

Spine and Paraspinal Sarcoma • Results – Median follow-up: 27 months – Local Recurrence:

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 Harvard Medical School

Sacral Chordoma T 1 post-gadolinium sagittal MRI Pre-treatment S 3 -4 chordoma 77. 4

Sacral Chordoma T 1 post-gadolinium sagittal MRI Pre-treatment S 3 -4 chordoma 77. 4 CGE (photons 30. 6 Gy protons 46. 8 CGE) Harvard Medical School

Sacral Chordoma Treatment Plan S 3 -4 chordoma 77. 4 CGE (photons 30. 6

Sacral Chordoma Treatment Plan S 3 -4 chordoma 77. 4 CGE (photons 30. 6 Gy protons 46. 8 CGE) Harvard Medical School

Sacral Chordoma Treatment Plan S 3 -4 chordoma 77. 4 CGE (photons 30. 6

Sacral Chordoma Treatment Plan S 3 -4 chordoma 77. 4 CGE (photons 30. 6 Gy protons 46. 8 CGE) Harvard Medical School

Sacral Chordoma T 1 post-gadolinium sagittal MRI S 3 -4 chordoma 77. 4 CGE

Sacral Chordoma T 1 post-gadolinium sagittal MRI S 3 -4 chordoma 77. 4 CGE (photons 30. 6 Gy protons 46. 8 CGE) No evidence of progressive disease at 19 months Harvard Medical School

Unresectable Sacral Osteosarcoma: Axial CT scan 19 year old with S 1 Osteosarcoma After

Unresectable Sacral Osteosarcoma: Axial CT scan 19 year old with S 1 Osteosarcoma After 12 weeks of chemotherapy Concurrent chemoradiation starting week 16 70. 2 CGE (photons 18 Gy protons 52. 2 CGE) Harvard Medical School

Unresectable Sacral Osteosarcoma: Treatment Plan (Axial) 19 year old with S 1 Osteosarcoma After

Unresectable Sacral Osteosarcoma: Treatment Plan (Axial) 19 year old with S 1 Osteosarcoma After 12 weeks of chemotherapy Concurrent chemoradiation starting week 16 70. 2 CGE (photons 18 Gy protons 52. 2 CGE) Harvard Medical School

Unresectable Sacral Osteosarcoma: Axial CT scan 19 year old with S 1 Osteosarcoma 29

Unresectable Sacral Osteosarcoma: Axial CT scan 19 year old with S 1 Osteosarcoma 29 months after treatment Chemotherapy + 70. 2 CGE (photons 18 Gy protons 52. 2 CGE) No evidence of progressive disease Harvard Medical School

Multiply (x 4) recurrent G 2 chondrosarcoma T 4 Harvard Medical School

Multiply (x 4) recurrent G 2 chondrosarcoma T 4 Harvard Medical School

Multiply recurrent G 2 chondrosarcoma T 4 Harvard Medical School

Multiply recurrent G 2 chondrosarcoma T 4 Harvard Medical School

Multiply recurrent G 2 chondrosarcoma T 4 Harvard Medical School

Multiply recurrent G 2 chondrosarcoma T 4 Harvard Medical School

Multiply recurrent G 2 chondrosarcoma T 4 Local recurrence 40 months after Surgery, plaque,

Multiply recurrent G 2 chondrosarcoma T 4 Local recurrence 40 months after Surgery, plaque, XRT Harvard Medical School

Multiply (x 6) recurrent G 2 chondrosarcoma T spine Harvard Medical School

Multiply (x 6) recurrent G 2 chondrosarcoma T spine Harvard Medical School

Dedifferentiated chondrosarcoma L spine Harvard Medical School

Dedifferentiated chondrosarcoma L spine Harvard Medical School

Multiply recurrent chondrosarcoma T spine Harvard Medical School

Multiply recurrent chondrosarcoma T spine Harvard Medical School

Multiply recurrent chondrosarcoma T spine Harvard Medical School

Multiply recurrent chondrosarcoma T spine Harvard Medical School

Spine and Paraspinal Sarcoma • Acute Complications – > Grade 3 • 1 painful

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 T 3 -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 Harvard Medical School

Spine and Paraspinal Sarcoma • Conclusions – High dose photon/proton XRT can be delivered

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 Harvard Medical School