harvard medical school phase ii study of proton radiation therapy for spine and paraspinal sarcomas...

Harvard Harvard Medical SchoolMedical School

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

SarcomasSarcomas

Thomas F. DeLaney, Norbert J. Liebsch, Ira J. Spiro, Thomas F. DeLaney, Norbert J. Liebsch, Ira J. Spiro, Patricia L. McManus, Judith Adams, Susan Dean, Patricia L. McManus, Judith Adams, Susan Dean,

Francis J. Hornicek, Francis X. Pedlow, Francis J. Hornicek, Francis X. Pedlow, Andrew L. Rosenberg, G. Petur Nielsen, Andrew L. Rosenberg, G. Petur Nielsen,

David C. Harmon, Sam S. Yoon, David C. Harmon, Sam S. Yoon, Kevin A. Raskin, Herman D. SuitKevin A. Raskin, Herman D. Suit


Sarcomas of the SpineSarcomas 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%


Sarcomas of the SpineSarcomas 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 CGE 5 Year LC 83%

– Trend to improved LC: primary, > 77 Gy, less residual


Spine and Paraspinal SarcomaSpine and Paraspinal Sarcoma

• Spine/Paraspinal Sarcoma (PI T. DeLaney MD)Spine/Paraspinal Sarcoma (PI T. DeLaney MD)– Surgery + IORT ( Dura Plaque) + Photon/ProtonSurgery + IORT ( Dura Plaque) + Photon/Proton

• IRB-approved protocolIRB-approved protocol• Surgery: Maximal debulking/spine stabilizationSurgery: Maximal debulking/spine stabilization• IORT: IORT: 9090Y dural plaque: 10 GyY dural plaque: 10 Gy• Photon/Proton RadiotherapyPhoton/Proton Radiotherapy

– 70.2 CGE (Microscopic residual)*70.2 CGE (Microscopic residual)*– 77.4 CGE (Gross residual disease)*77.4 CGE (Gross residual disease)*

* Doses modified for concurrent chemotherapy, diabetes, * Doses modified for concurrent chemotherapy, diabetes, connective tissue diseases, radioresponsive histologiesconnective tissue diseases, radioresponsive histologies


Ideal Dose Distribution


L1 Angiosarcoma L1 Angiosarcoma

Proton IMRTASTRO 2003


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

IMPTIMPT IMXTIMXT


Spine/Paraspinal Sarcoma: Clinical TrialSpine/Paraspinal Sarcoma: Clinical Trial

• Radiation TherapyRadiation Therapy• CTV1 (clinical target volume)CTV1 (clinical target volume)

– Tissues suspected of microscopic involvementTissues suspected of microscopic involvement– Doses: 50.4 CGE at 1.8 Gy per fractionDoses: 50.4 CGE at 1.8 Gy per fraction

• Could be given with photonsCould be given with photons• Majority of pts received ~30.6 Gy with photons (conformal or IMRT)Majority of pts received ~30.6 Gy with photons (conformal or IMRT)

– Treated pre-operatively when possible to doses of:Treated pre-operatively when possible to doses of:– 19.8 Gy : Sacrum19.8 Gy : Sacrum 45-50.4 Gy: Thoracolumbar spine45-50.4 Gy: Thoracolumbar spine

• Reduces risk of tumor seeding into woundReduces risk of tumor seeding into wound• Dose selection based upon risk of wound healing delayDose selection based upon risk of wound healing delay• CTV dose reduced to 46.8 Gy with IDDM/autoimmune diseaseCTV dose reduced to 46.8 Gy with IDDM/autoimmune disease



• Radiation TherapyRadiation Therapy– CTV (clinical target volume)CTV (clinical target volume)

• Controlled information on extent of CTV not availableControlled information on extent of CTV not available• CTV based upon the patterns of failure in surgical and CTV based upon the patterns of failure in surgical and

radiation therapy seriesradiation therapy series• Generally included the entire involved vertebral body and Generally included the entire involved vertebral body and

at least hemi-sacral segment in the CTVat least hemi-sacral segment in the CTV• Areas of extra-osseous extension into soft tissue are Areas of extra-osseous extension into soft tissue are

included with 1 cm margin or to fascial barrierincluded with 1 cm margin or to fascial barrier• Scar coverage for patients receiving post-op XRT Scar coverage for patients receiving post-op XRT

dependent upon histology, grade, length of scardependent upon histology, grade, length of scar



• Radiation TherapyRadiation Therapy• GTV (gross tumor volume)GTV (gross tumor volume)

– CTV2: Encompasses original gross tumorCTV2: Encompasses original gross tumor• Boosted to dose of 70.2 CGE at 1.8 CGE q.d. with protonsBoosted to dose of 70.2 CGE at 1.8 CGE q.d. with protons• Giant cell tumor, Ewing’s sarcoma : 61.2 GyGiant cell tumor, Ewing’s sarcoma : 61.2 Gy

– CTV3: Residual gross disease after surgeryCTV3: Residual gross disease after surgery• Boosted to dose of 77.4 CGE at 1.8 CGE q.d. with protonsBoosted to dose of 77.4 CGE at 1.8 CGE q.d. with protons• If IDDM/autoimmune disease or concurrent chemotherapy (i.e. If IDDM/autoimmune disease or concurrent chemotherapy (i.e.

osteosarcoma), doses reduced by 8%: total 70.2-72.0 CGEosteosarcoma), doses reduced by 8%: total 70.2-72.0 CGE

• ChemotherapyChemotherapy– Adriamycin not delivered concurrentlyAdriamycin not delivered concurrently


Spine/Paraspinal Sarcoma:Spine/Paraspinal Sarcoma: CT myelogram for Radiation Planning CT myelogram for Radiation Planning

T6 spine/paraspinalChondrosarcoma

CT myelogram for lesions above the conus to outlinespinal cord


Spine/Paraspinal Sarcoma:Spine/Paraspinal Sarcoma: Treatment Position Treatment Position

LPO Proton FieldThoracic Chondrosarcoma


Spine/Paraspinal Sarcoma:Spine/Paraspinal Sarcoma: Treatment Planning Treatment Planning

S1 Chondrosarcoma

Treatment Plan


Spine/Paraspinal Sarcoma:Spine/Paraspinal Sarcoma: Set-Up Verification Set-Up Verification

Set-up Radiograph with Digitized Set-up Points, Actual(red) and Desired (blue) Isocenter Axes

Sacral Chondrosarcoma



• Normal tissue constraintsNormal tissue constraints• Spinal cordSpinal cord

– Surface: 63 CGE Center: 54 CGE (for length up to 5 cm) Surface: 63 CGE Center: 54 CGE (for length up to 5 cm)

• Cauda equinaCauda equina– Limit dose to contralateral nerves when possibleLimit dose to contralateral nerves when possible

• RectumRectum– Use omental flap to displace rectum for sacral chordomasUse omental flap to displace rectum for sacral chordomas

• Small bowelSmall bowel– 50.4 CGE50.4 CGE

• SkinSkin– Avoid full dose on skin overlying sacrumAvoid full dose on skin overlying sacrum



• Beam SelectionBeam Selection– Protons not stopped on the spinal cord Protons not stopped on the spinal cord

• Concern about end of range uncertaintyConcern about end of range uncertainty• RBE variation at end of proton rangeRBE variation at end of proton range

– Patch fields contour dose around spinal cordPatch fields contour dose around spinal cord


ThoracicThoracic Chondrosarcoma Chondrosarcoma

Treatment Plan (Protons)60 year old diabetic female with T9 Chondrosarcoma

Radiated after laminectomy

72 CGE (IMRT photons 45 Gy protons 27 CGE)


9090Y Plaque IrradiationY Plaque Irradiation

Plaque on Dura


ResultsResults

•Plaques

Comparative depth doses192Ir 90Y

•2 mm 80% 27%•4 mm (cord surface) 60% 8%•8 mm (cord center) 50% 0%


Exposed Gafchromic FilmExposed Gafchromic Film

Surface Exposure

%Depth Dose Exposure



• Accrual targetAccrual target 50 patients50 patients– StatisticsStatistics

• Anticipated local failure with lower dose photons Anticipated local failure with lower dose photons estimated to be 50% with spine chordomas at 5 yearsestimated to be 50% with spine chordomas at 5 years

• 80% power to detect decrease to 30% local failure rate80% power to detect decrease to 30% local failure rate



• Accrual 50 PatientsAccrual 50 Patients 12/97-3/2005 12/97-3/2005 – ChordomaChordoma 2828 ChondrosarcomaChondrosarcoma 1414– LiposarcomasLiposarcomas 2 2 AngiosarcomaAngiosarcoma

1 1– Ewing’s SarcomaEwing’s Sarcoma 1 1 Giant cell tumorGiant cell tumor 1 1– Malignant schwannoma Malignant schwannoma 1 1 OsteosarcomaOsteosarcoma 1 1– Spindle and round cell Spindle and round cell 1 1

• Thoracic 12Thoracic 12 Lumbar 12Lumbar 12 Sacrum 26Sacrum 26• Primary Primary 3737 Locally recurrent 13Locally recurrent 13• Extent of surgeryExtent of surgery

– Grossly resected Grossly resected 2525– Subtotally excised Subtotally excised 1212– Biopsy onlyBiopsy only 1313

• All but 1 patient completed Rx (social reasons)All but 1 patient completed Rx (social reasons)– Dose delivery within 3% of protocol target in all patientsDose delivery within 3% of protocol target in all patients


Spine and Paraspinal SarcomaSpine and Paraspinal Sarcoma• ResultsResults

– Median follow-up: 27 monthsMedian follow-up: 27 months– Local Recurrence: 6 at 8-32 months after start of XRT Local Recurrence: 6 at 8-32 months after start of XRT

• 2 also with distant metastases 2 also with distant metastases • 2 chordomas, 4 chondrosarcomas2 chordomas, 4 chondrosarcomas• 3/13 patients treated for recurrent tumor vs. 3/27 for primary tumor3/13 patients treated for recurrent tumor vs. 3/27 for primary tumor

– Distant Metastases: 3 isolated at 11-35 m after start of XRT Distant Metastases: 3 isolated at 11-35 m after start of XRT – LR, DM, and tumor-associated deaths were all in pts with LR, DM, and tumor-associated deaths were all in pts with

gross residual disease except 1 pt with dedifferentiated gross residual disease except 1 pt with dedifferentiated chondrosarcoma with tumor cut through at initial surgerychondrosarcoma with tumor cut through at initial surgery

– SurvivalSurvival• 3 died of progressive tumor (2 chondrosarcoma, 1 malig schwannoma)3 died of progressive tumor (2 chondrosarcoma, 1 malig schwannoma)• 2 died unrelated causes (cardiac, oral cancer)2 died unrelated causes (cardiac, oral cancer)• 1 lost to follow-up1 lost to follow-up


SacralSacral Chordoma Chordoma

T1 post-gadolinium sagittal MRI

Pre-treatment

S3-4 chordoma

77.4 CGE (photons 30.6 Gy protons 46.8 CGE)



Treatment Plan

S3-4 chordoma




T1 post-gadolinium sagittal MRI

S3-4 chordoma


No evidence of progressive disease at 19 months


Unresectable SacralUnresectable SacralOsteosarcoma:Osteosarcoma:

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)



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)



Axial CT scan19 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


Multiply (x4) recurrent G2 chondrosarcoma T4Multiply (x4) recurrent G2 chondrosarcoma T4


Multiply recurrent G2Multiply recurrent G2 chondrosarcoma T4chondrosarcoma T4


Multiply recurrent G2 chondrosarcoma T4Multiply recurrent G2 chondrosarcoma T4


Multiply recurrent G2chondrosarcoma T4Multiply recurrent G2chondrosarcoma T4

Local recurrence 40 months afterSurgery, plaque, XRT


Multiply (x6) recurrent G2 chondrosarcoma T spineMultiply (x6) recurrent G2 chondrosarcoma T spine


Dedifferentiated chondrosarcoma L spineDedifferentiated chondrosarcoma L spine


Multiply recurrent chondrosarcoma T spineMultiply recurrent chondrosarcoma T spine



• Acute ComplicationsAcute Complications– >> Grade 3 Grade 3

• 1 painful sacral stress fracture without late sequelae.1 painful sacral stress fracture without late sequelae. • Late ComplicationsLate Complications

– >> Grade 3 Grade 3• 1 sacral neuropathy: L1 sacral neuropathy: Large, unresected sacral chordoma ( 77.4 arge, unresected sacral chordoma ( 77.4

CGE) LE weakness, stress urinary incontinence, poor rectal tone at CGE) LE weakness, stress urinary incontinence, poor rectal tone at 5.5 years 5.5 years

• 1 erectile dysfunction: 65 y.o. unresected sacral chordoma (77.4 1 erectile dysfunction: 65 y.o. unresected sacral chordoma (77.4 CGE) 4 yrsCGE) 4 yrs

– Grade 2Grade 2• 1 erectile dysfunction: 46 y.o. recurrent T3-5 chondrosarcoma and 1 erectile dysfunction: 46 y.o. recurrent T3-5 chondrosarcoma and

cord compressions (77.4 CGE) at 2 years; responsive to sildenafilcord compressions (77.4 CGE) at 2 years; responsive to sildenafil• One late sacral stress fracture after fall, 3 months after XRT and One late sacral stress fracture after fall, 3 months after XRT and

subtotal intralesional excision/MMA packing; managed with nail; subtotal intralesional excision/MMA packing; managed with nail; chronic painchronic pain



• ConclusionsConclusions– High dose photon/proton XRT can be deliveredHigh dose photon/proton XRT can be delivered– Morbidity to date appears acceptable. Morbidity to date appears acceptable. – Encouraged to date by the treatment results with Encouraged to date by the treatment results with

these challenging tumorsthese challenging tumors• Await further follow-up Await further follow-up • Prefer to radiate at time of initial presentationPrefer to radiate at time of initial presentation

– Potential concern about late sacral nerve toxicity in Potential concern about late sacral nerve toxicity in patients receiving 77.4 Gypatients receiving 77.4 Gy

harvard medical school phase ii study of proton radiation therapy for spine and paraspinal sarcomas...

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