Thomas F. DeLaney MD, Aashish D. Bhatt MD, Alex Jacobson BS, Richard Y. Lee MD, PhD, Christine Giraud BS, Joseph H. Schwab MD, MS, Francis J. Hornicek MD, PhD, Petur Nielsen MD, Edwin Choy MD, PhD, David Harmon MD and Yen-Lin E. Chen MD Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 1 Connective Tissue Oncology Society 2014, Berlin, Germany

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 Surgery is the primary local treatment for chondrosarcoma (CS)  The anatomic location or size of the tumor, however, may make it difficult or impossible to achieve negative surgical margins  RT has been used as an adjuvant or definitive Rx in such cases  Rosenberg et al: 98% local control in 200 skull base CS pts with high dose proton RT (Am J Surg Pathol 1999)- small, lower grade  Goda et al (Princess Margaret Hosp): 90% crude local control in 60 pts with extracranial CS treated with adjuvant RT (Cancer, 2011) ◦ R0 50%, R1 28%, R2 13% ; 40% low ext/pelvis and 17% spine 3

 Study intent to assess outcomes in high risk CS pts ( high proportion of R2, spine) Rx’ed with 3D passively scattered protons  Radiation doses required for control of microscopic residual disease > ~66 Gy and for gross disease > 70 Gy  These doses may be difficult to achieve in axial locations such as the mobile spine where spinal cord radiation tolerance or the sacrum and pelvis where bowel tolerance may be dose limiting  These RT doses can often be achieved with proton beam therapy (PBT) due to the physical characteristics of sharp lateral dose fall off and distal sparing with no exit dose beyond the Bragg Peak 4

GyRBE/11 fx preop protons to CTV1 (tumor bed and adjacent tissues) -Posterior decompression S1-S4 and subtotal intralesional resection; bone graft/cement GyRBE/17 fx postop protons to CTV1 27 Gy RBE/15 fx postop protons to CTV2, the tumor bed/residual tumor 33 yo Female Sacral CSA, Grade 1-2 treated to 77.4 GyRBE NED 10 yrs After Rx

 Forty four patients (N=44) were identified who received PBT as part of their treatment for CS from 1990 to 2012  Retrospective review of their medical and RT treatment records was then conducted  Multivariate analyses performed to identify patient and tumor related factors predicting for improved local control and overall survival. 6

 Median age yrs (4-83) Male 45%: Female 55%  Site: Spine/Sacrum 80%Pelvis 14%Other3%  Median tumor size was 13 cms (range: 1-27)  Mixed myxoid/hyaline 43%Hyaline 25%Other 32%  Tumor Grade - I (27%), II (59%) and III (14%) 7

 Primary tumor: 73%Recurrent after prior surgery: 27%  Surgery: resection status ◦ Gross total 50%Subtotal 41%Bx only 9%  Margin status ◦ R0: 25% ◦ R1: 14% ◦ R2: 50% Unknown: 11%  Median follow-up was 29.1 months (range: ) 8

 RT Schedule ◦ Pre-op +/- postop boost : 50% ◦ Post-operative: 41% ◦ Definitive, non-surgical Rx 9%  Median RT dose:70.2 GyRBE at 1.80 Gy per fraction ◦ Maximum RT dose: 77.4 GyRBE  Photon RT + Proton : 77% Proton only: 23%  Intra-operative RT (IORT) was used in 5 patients 9

 Local controlOverall Survival ◦ 2 year: 76% ◦ 2 year: 90% ◦ 5 year: 57% ◦ 5 year: 68%  Toxicity: ◦ Acute wound complication 16% ◦ Neuropathy (G2 sciatic, G3 sacral) 5% (74, 77.4 GyRBE)  No myelopathies ◦ Sacral fracture 5% ◦ Chronic pain 5% ◦ Hypothyroidism 2% 10

11 Local Control - 2 years – 76 % 5 years – 57 %

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13 VariableHazard Ratio (HR) 95% Confidence Interval (C.I.) p-value Sex Female (ref.) Male0.34( )0.233 Tumor Grade I (ref.) II2.29( )0.476 III26.46( )0.019 Primary /Recurrent Primary (ref.) Recurrence1.92( )0.391 Site of Tumor Non-Spine (ref.) Spine1.45( )0.777 Resection Margin R0 (ref.) R10.88( )0.928 R21.69( )0.611 Not Reported0.25( )0.405 Grade III tumors were associated with decreased local control, (p=0.019).

14 Female gender (p=0.037) and grade III tumors (p=0.005) were associated with a poorer overall survival

Our series is the largest report on the use of proton radiation in the management of non-skull base chondrosarcomas Protons, in combination with surgery in most pts in this series, resulted in LC in 57% despite high risk factors (i.e. 50% R2, spine sites) Protons allowed high RT doses in spinal/sacral tumors No myelopathy but 5% risk of neuropathy, sacral fracture, chronic pain 16% risk of acute wound healing problems Use only 19.8 Gy preop for sacral lesions unless subcutaneous sparing possible as well as flaps (i.e. rectus) in conjunction with plastic surgery Female gender was predictive for decreased survival while grade III tumors predicted for decreased local control and survival 15