1. CTOS 2013 Radiation Oncology Session Discussion Elizabeth H Baldini, MD, MPH Associate Professor of Radiation Oncology Harvard Medical School Brigham and Women's Hospital and Dana-Farber Cancer Institute

2. I have no disclosures.

3. “Making the Case for IMRT”

4. 3D Conventional vs IMRT 3D (Conventional) Fixed beams deliver uniform dose Conform dose to the target Dose gradient less steep  set-up less crucial Less expensive IMRT Beams deliver variable dose intensity Sculpts dose to better conform to target Dose gradient is steep  set-up must be precise More expensive

5. 3D vs IMRT Dose Distributions* Isodoses Red: 100%; Light blue: 20-30% *Hong, IJROBP 59:752; 2004

6. IMRT and Local Control

7. Late Effects of Pre-operative Image- Guided Radiation Therapy (IGRT) in Extremity Sarcoma Patients: Results of RTOG 0630 Wang D, Zhang Q, Eisenberg B, Kane J, Li A, Lucas D, Freeman C, Trotti A, Hitchcock Y, Kirsch D RTOG multi-center trial

8. RTOG 0630 79 Patients with extremity STS Treated with pre-op RT + S RT Technique: 75% IMRT 3-year LR: 7 %

9. Quantitative Dosimetric Analysis of Patterns of Local Relapse After IMRT for Primary Extremity Soft Tissue Sarcomas Lanning R, Berry S, Folkert M, Alektiar K Memorial Sloan-Kettering Cancer Center, NY

10. MSKCC 165 Patients extremity STS Treated with S + RT –79% post-op RT RT technique: 100% IMRT 5-year LR: 8.4%

11. Local Control Rates for Modern Series 3D Conventional and IMRT: Similarly Excellent 5-yr LR RT Modality 3D vs IMRT RT Sequence Patient Number NCIC RCT, 2004 O’Sullivan 6%, 7%100% 3DPre-op + Post-op 190 BWH/DFCI, 2013 Baldini 10%84% 3DPre-op103 MSKCC, 2013 Alektiar 14.3%100% 3D88% Post-op 155 MGH, 2010 Kim 11.5%88% 3DPre-op56 PMH, 2013 O’Sullivan 11.8%100% IMRT (flap sparing) Pre-op59 MSKCC, 2013 Lanning 8.4%100% IMRT79% Post-op 165 RTOG 0630, 2013 Kirsch 7% (3-yr) 75% IMRTPre-op79

12. IMRT and Late Effects Subcutaneous Fibrosis, Joint Stiffness, Edema Bone Fracture Wound Complications

13. Subcutaneous Fibrosis, Joint Stiffness, Edema

14. Late Effects of Pre-operative Image- Guided Radiation Therapy (IGRT) in Extremity Sarcoma Patients: Results of RTOG 0630 Wang D, Zhang Q, Eisenberg B, Kane J, Li A, Lucas D, Freeman C, Trotti A, Hitchcock Y, Kirsch D RTOG Multi-Center Trial

15. RTOG 0630 vs NCI Canada Randomized Trial* Late Toxicity at 2 Years RTOG 0630Pre-op Arm NCIC > Grade 2 Toxicity10.5%37% Subcutaneous Fibrosis 5.4%**31.5% Joint Stiffness5.4%**17.8% Edema5.2%**15.1% *O’Sullivan, Lancet 2002, 359:2235; Davis, Radiother Oncol 2005, 75:48 **Wang, IJROBP 2013, 87:S63 Authors compare their results to NCIC trial

16. RTOG 0630 vs NCI Canada Randomized Trial* Study Details: Some Major Differences RTOG 0630Pre-op Arm NCIC Study Era2008-101994-97 Evaluable Patients5773 Follow-upMedian 27 mosMinimum 21 mos Clinical Target Volume Smaller (2-3 cm margin on GTV) Larger (4 cm margin on GTV) RT Technique75% IMRT100% 3D Late effect assessment schedule & tools Same *O’Sullivan, Lancet 2002, 359:2235; Davis, Radiother Oncol 2005, 75:48

17. Other Late Toxicity Results Modern Era with IMRT InstitutionPMH*MSKCC**RTOG 0630***Pre-op Arm NCIC Study Era2005-092002-102008-101994-1997 Patient Number511655773 Treatment Modality 100% IMRT (sparing flap) 100% IMRT (79% post-op) 75% IMRT100% 3D Subcutaneous Fibrosis 9.3%NS5.4%31.5% Joint Stiffness5.6%14.5%5.4%17.8% Edema11.1%7.9%5.2%15.1% *O’Sullivan Cancer 2013, 119:1878; **Alektiar IJROBP 2013, 87:S63 2008,26:344-0 and personal communication ***Wang, IJROBP 2013, 87:S63 Use of IMRT may be the main reason for reduced toxicity

18. Bone Fracture

19. Evaluation of Femur Fracture Risk in Soft Tissue Sarcoma of the Thigh Treated with IMRT Folkert M, Singer S, Brennan M, Boland P, Alektiar K Memorial Sloan-Kettering Cancer Center, NY

20. MSKCC Results 82 patients treated with S + RT RT technique: 100% IMRT Fracture Rate 6.1% Expected Fracture Rate using PMH Nomogram: 26.4% This finding is not surprising …

21. PMH Nomogram Derived from 3D Era Patients treated 1986-2006 RT Technique: 100% 3D RT Examined variables we might now consider proxies for more accurate variables –Sex –Age –Compartment –Tumor Size –Radiation Dose –Periosteal Stripping

22. A Modern Era Comparison Subsequent PMH report from 2009* Examined dosimetric parameters Lower risk of bone fracture if: »V40 < 64% »Mean bone dose < 37 Gy »Max bone dose < 59 Gy Agree with MSKCC authors that clinical variables in nomogram are less predictive Dosimetric variables are more predictive *Dickie, IJROBP 75:1119; 2009

23. IMRT, Designed with Evidence-Based Bone Avoidance Objectives, Reduces the Risk of Bone Fracture in the Management of Extremity Soft Tissue Sarcoma Dickie C, Sharpe M, Chung P, Griffin A, Parent A, Catton C, Ferguson P, Wunder J, O’Sullivan B Princess Margaret Hospital, Toronto

24. PMH Results 230 patients treated with IMRT Employed bone avoidance objectives: »V40 < 64% »Mean bone dose < 37 Gy »Max bone dose < 59 Gy Fracture rate: 1.7% Lower than prior report of 6.3% (3D) Demonstrates –Validity of bone avoidance objectives –Objectives largely achievable with IMRT –Fracture rate much lower than prior rates in 3D series

25. Wound Complications

26. In Depth Analysis of Wound Complications Following Preoperative Radiotherapy for Lower Extremity Soft Tissue Sarcoma Patients Dickie C, Griffin A, Moseley J, Biau D, Parent A, Sharpe M, Chung P, Catton C, Ferguson P, Wunder J, O’Sullivan B Princess Margaret Hospital, Toronto

27. PMH Methods 59 Patients Treated with IMRT to spare the surgical flap PTV coverage prioritized over flap-sparing

28. PMH Results Wound Complications (WC): – 30.5% (flap-sparing IMRT) – 43% from NCIC trial (3D) WC were further reduced when 92% of flap spared –14.3% when <1% overlap of flap and PTV* Flap-sparing and ability to reduce WC can ONLY be achieved using IMRT *O’Sullivan Cancer 2013, 119:1878

29. Conclusions IMRT  Excellent Local Control –As good as, if not better than 3D –(Lanning, Kirsch, O’Sullivan) IMRT  Less Late Toxicity vs 3D –Subcutaneous Fibrosis, Joint Stiffness, Edema (Kirsch, Alektiar, O’Sullivan) –Bone Fracture (Folkert, Dickie) –Wound Complications (Dickie)

30. Conclusions Abstracts presented today combined with other published literature: “Make the Case for IMRT”

31. Clinical Implications IMRT Should be Standard of Care for Most Cases of Extremity STS

32. Dana-Farber / Brigham and Women’s Cancer Center: Center for Sarcoma and Bone Oncology Surgical Oncology Monica Bertagnolli, MD Chandrajit Raut, MD, MSc Medical Oncology James Butrynski, MD David D’Adamo, MD George Demetri, MD Suzanne George, MD Jeffrey Morgan, MD Andrew Wagner, MD, PhD Pathology Christopher Fletcher, MD Jonathan Fletcher, MD Jason Hornick, MD, PhD Alessandra Nascimento, MD Radiation Oncology Elizabeth Baldini, MD, MPH Philip Devlin, MD Karen Marcus, MD Orthopedic Oncology Marco Ferrone, MD John Ready, MD ebaldini@partners.org