1. Quantitative Dosimetric Analysis Of Patterns Of Local Relapse After IMRT For Primary Extremity Soft Tissue Sarcomas Ryan M. Lanning, Sean L. Berry, Michael R. Folkert, and Kaled M. Alektiar Dept. of Radiation Oncology and Medical Physics Memorial Sloan-Kettering Cancer Center

2. Disclosures We have no conflicts of interest to disclose.

3. Characterizing Local Recurrence Marginal Central Distant Scar RT Field

4. Objectives Characterize local recurrence of extremity STS treated with adjuvant IMRT based on dose received to the recurrence volume. Determine any patient, tumor, or treatment characteristics that may predict local recurrence.

5. Soft Tissue Sarcoma Study Population Time Period: 2/2002 – 12/2010 # of patients:165 Male:101 (61%) Female:64 (39%) Median Age:55 (19-88) years Pre-op IMRT: 34 (21%) Median: 50Gy (48-50) Post-op IMRT: 131 (79%) Median: 63Gy (27-66.6)

6. Tumor and Treatment Characteristics %n Tumor Size:>10 cm 44%73 Grade:High 87%143 Depth:Deep 91%150 Site:Lower extremity 74%123 Margin Status:Positive / Close 52%85 Adjuvant Chemo:Yes 27%45

7. Original RT Fields and LR Patterns

8. Recurrence Based on Dose Distribution Recurrence CTV PTV

9. Dosimetric Characterization of Recurrence Dose (% Prescription) Volume (%) V95 Relationship to 95% IDL* Central = Completely within Marginal = Crosses Distant = Completely outside * : Milano MT et al. IJROBP 2010

10. Outcomes n%5-yr LR Median time to LR (mo) Overall13- 8.4% (95% CI: 3.8 - 13) 19 (range: 9 - 61) Central431 2.9% (95% CI: 0 - 5.7) 24 (range: 13 - 28) Marginal861 5.0% (95% CI: 1.4 - 8.6) 18 (range: 9 - 61) Distant18 0.7% (95% CI: 0 – 2.1) 19 Median Follow-up = 42 months

11. Predictors of Local Recurrence FactorEvents5-yr LR (%)P-value Age  50 yrs 2 / 544 0.19 > 50 yrs 11 / 11110 Size  10cm 5 / 925 0.12 > 10 cm8 / 7313 Margin Negative4 / 804 0.18 Positive / close9 / 8512 IMRT Scheduling Preop4 / 3415 0.24 Postop9 / 1317 Histology Liposarcoma2 / 50 5 0.41 MFH4 / 3513 Myxofibrosarcoma4 / 3313 Other3 / 466 Depth: p = 0.24Chemo: p = 0.66Site: p = 0.75Grade: p = 0.95

12. Conclusions Dosimetric analysis provides a quantitative tool for characterizing local recurrence Traditional predictors of local recurrence in STS appear to exert less influence in the setting of IMRT Tumor Biology Treatment

13. Acknowledgements My collaborators: Dr. Sean Berry and Dr. Michael Folkert My mentor: Dr. Kaled Alektiar CTOS selection committee, Committee chairs, and our discussant

14. Room for Improvement? HistologySite dMax (cm) GradeMarginIMRT Vrecur 95% IDL LR 1Liposarcoma Thigh25LowClose / +Post-op100%Central 2Liposarcoma Thigh18HighClose / +Post-op100%Central 3Myxofibrosarcoma Thigh10.5HighClose / +Post-op100%Central 4Myxofibrosarcoma Hand1.6HighClose / +Pre-op100%Central 5MFH Thigh12HighClose / +Post-op94.4%Marginal 6MFH Thigh15HighNegativePost-op93.6%Marginal 7MFH Thigh15.3HighNegativePost-op92.3%Marginal 8STS (NOS) Arm6.5LowNegativePost-op90.5%Marginal 9STS (NOS) Thigh5.1HighClose / +Post-op74.1%Marginal 10Fibrosarcoma Triceps8HighClose / +Pre-op35.3%Marginal 11Myxofibrosarcoma Thigh21HighClose / +Pre-op18.5%Marginal 12Myxofibrosarcoma Thigh17.9HighNegativePost-op0.1%Marginal 13MFH Knee6.6HighClose / +Pre-op0%Distant

15. Recurrence Characteristics HistologyLR Site LR Confirmation Time LR to MRI (d) Vrecur (cc) Salvage 1 Liposarcoma CentralClinical023.2 S 2 Liposarcoma CentralBiopsy1048.2 S/B 3 Myxofibrosarcoma CentralClinical05.1 C/S/B 4 Myxofibrosarcoma CentralBiopsy-371.2 S 5 MFH MarginalBiopsy127.6 S 6 MFH MarginalClinical032.0 C 7 MFH MarginalClinical067.3 C 8 STS (NOS) MarginalBiopsy053.0 S 9 STS (NOS) MarginalBiopsy-157.6 R/S 10 Fibrosarcoma MarginalBiopsy436.0 S 11 Myxofibrosarcoma MarginalClinical047.7 S/C 12 Myxofibrosarcoma MarginalBiopsy737.8 R/S 13 MFH DistantBiopsy-14132.4 None S = SurgeryC = ChemotherapyR = EBRTB = Brachytherapy

16. CTV: GTV + 1-1.5 cm in radial axis PTV: CTV plus 1 cm margin in all directions Volume Expansion: Pre-op IMRT CTV: GTV + 4 cm in long axis

17. CTV : Tumor bed + 4 cm in long axis PTV: CTV plus 1 cm margin in all directions CTV: Tumor bed + 1-1.5 cm in radial axis Volume Expansion: Postop IMRT

18. Local Recurrence: EBRT vs IMRT Competing risks, cumulative incidence, Gray’s test and Fine and Gray regression were used to estimate 5-y local recurrence: – IMRT: 7.6% (95% CI 3.4-11.8%) – Conventional EBRT: 15% (95% CI 9.2-20.9%) P = 0.049 Courtesy of MR Folkert

19. Discussion points – Basis of Improved Outcome? Improved conformality and homogeneity of dose may be the basis of improved local control. 1.Swanson EL et al, Int J Radiation Oncology Biol Phys. 2012 83(5):1549-57. 2.Stewart AJ et al, Radiother Oncol. 2009 Oct;93(1):125-30. 3.Griffin AM et al, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):847-56. Conformity/ConformalityHomogeneity/Heterogeneity StudyIMRTConventional EBRTIMRTConventional EBRT Swanson et al 1 0.750.510.0660.073 Stewart et al 2 1.33-1.591.761.036-1.0451.052 Griffin et al 3 1.271.76-2.34n/a Courtesy of MR Folkert

20. Predictors of Local Recurrence FactorEvents5-yr LR (%)95% CIP-value Age  50 yrs 2/5441 - 7 0.19 > 50 yrs 11/111107 - 14 Site Upper3/4262 - 10 0.75 Lower10/12396 - 12 Size  10cm 5/9252 - 8 0.12 > 10 cm8/73138 - 17 Grade Low2/2250 - 9 0.95 High11/14396 - 12 Margin Negative4/8042 - 6 0.18 Positive / close9/85128 - 16 IMRT Scheduling Preop4/34158 - 22 0.24 Postop9/13174 - 9 Histology Liposarcoma2/50 51 - 8 0.41 MFH4/35137 - 19 Myxofibrosarcoma4/33137 - 18 Other3/4662 - 11 Depth: p = 0.24Chemo: p = 0.66