1. Malignancy Grade and Histologic Subtype of Primary Retroperitoneal Sarcoma (RPS) are Predictive of Pattern of Recurrence: a Large Retrospective Study from the Transatlantic RPS Working Group Gronchi A, Strauss D, Miceli R, Bonvalot S, Swallow CJ, Hohenberger P, Van Coevorden F, Rutkowski P, Callegaro D, Pollock RE and Raut CP

2. Disclosures No disclosures

3. Background

4. Surgery is the primary and only curative treatment of localized disease Quality of local treatments and biology of the tumor are the major determinants of outcome Gronchi A and Pollock RE. Ann Surg Oncol 2013; 20(7): 2011-2013

5. Controversy What is the appropriate extent of resection? Great Debates SSO 2013

6. Toulemond et al. Ann Oncol 2014; 25: 735-742

7. Questions What are the patterns of recurrence and survival? Do different strategies by institution translate into different outcomes?

8. Methods

9. Trans-Atlantic RPS Working Group

10. 1007 consecutive primary adult-type RPS from 8 centers –Ewing/PNET, alveolar/embryonal rhabdo, desmoid, GYN sarcoma and GIST excluded

11. Patient Characteristics 2002-2011 M 52%, F 48% Median age: 58 (IQR 48-67) Median size: 20 cm (IQR 13-30 cm) Macroscopic complete resection: 95% –Tumor rupture with spillage in the operative field: 6% –Contamination: 4% Multifocality: 9% Distance from home > 100km (62 miles): 46%

12. Patient Characteristics Postoperative complication ≥3 according to CTCAE: 21% Reoperation: 11% Median number of resected organs: 2 (IQR 1-4) CT done: 18% (Anthracyclin based: 12%) RT done: 32% (preoperatory: 20%) Median FU: 58 months (IQR 36-90) Grading: 1 (34%), 2 (38%), 3 (28%)

13. Histology Distribution

14. Statistical Analysis OS estimated with KM curves CCI of LR and DM calculated in a competing risk framework Multivariable Cox regression analysis of OS, LR and DM

15. Results

16. Over Entire Cohort 5-yr 66.8% (95%CI 63.5-70.2%) 8-yr 56.1% (95%CI 52.0-60.6%) 10-yr 45.8% (95%CI 39.7-52.8%) 5-yr CCI 25.9% (95% CI 23.1-29.1%) 8-yr CCI 31.3% (95%CI 27.8-35.1%) 10-yr CCI 35.0% (95%CI 30.5-40.1%) 5-yr CCI 21.0% (95% CI 18.4-23.8%) 8-yr CCI 21.6% (95%CI 19.0-24.6%) 10-yr CCI 21.6% (95%CI 19.0-24.6%) 0.0 0.1 0.2 0.3 0.4 0.5 Time (months) CCI 01224364860728496 0.0 0.1 0.2 0.3 0.4 0.5 Time (months) CCI 01224364860728496 Time (months) OS 01224364860728496 0.0 0.2 0.4 0.6 0.8 1.0 Overall Survival Local RecurrenceDistant Metastasis

17. Current status – overall survival SEER: Primary 1365 RPS 5yr OS – 47% (2010) Transatlantic Sarcoma Group >1000 Primary RPS 5yr OS – 67% (2014)

18. OS by Histology WD LPS: 83.4% SFT: 76.5% GIII DD LPS: 30.2% LMS: 43.4% GII DD LPS: 51.1%

19. WD LPS: 34.5% SFT: 14.0% GIII DD LPS : 38.0% LMS: 11.6% GII DD LPS: 49.1% LR by Histology

20. DM by Histology WD LPS: 0.4% SFT: 12.7% GIII DD LPS: 32.6% LMS: 52.6% GII DD LPS: 9.1%

21. Results from the Cox proportional hazards models on the three endpoints analyzed. OSLRDM HR95% CIPHR95% CIPHR95% CIP Age, years <0.001 0.004 0.055 67 vs. 48*1.49(1.25, 1.77) 1.27(1.07, 1.50) 1.21(1.00, 1.47) Size, cm 0.021 0.115 0.090 30 vs. 13*1.28(0.99, 1.66) 1.31(1.00, 1.71) 0.94(0.71, 1.25) Surgical resection <0.001 0.059 Incomplete vs. complete2.54(1.61, 4.00) 3.71(2.35, 5.83) 2.02(0.97, 4.17) FNCLCC grade <0.001 II vs. I2.50(1.44, 4.34) 2.54(1.52, 4.25) 2.21(1.26, 3.87) Multifocality<0.001 0.003 Yes vs.no1.91(1.34-2.74)2.16(1.51-3.09)1.93(1.25-2.96) Histological subtype 0.076 0.009 <0.001 WD liposarcoma vs. SFT1.65(0.44, 6.18) 2.35(1.04, 5.32) 0.53(0.20-1.37) DD liposarcoma vs. SFT1.64(0.80, 3.35) 1.98(0.92, 4.24) 0.98(0.45, 2.13) Leiomyosarcoma vs.SFT1.98(0.95, 4.11) 1.06(0.47, 2.40) 2.62(1.22, 5.61) MPNST vs. SFT1.69(0.68, 4.19) 1.08(0.38, 3.04) 0.93(0.32, 2.70) Other vs. SFT2.87(1.31, 6.29) 1.67(0.67, 4.15) 2.19(0.95, 5.03) CT 0.208 0.175 0.429 Yes vs.no1.21(0.90, 1.64) 1.28(0.90, 1.83) 1.14(0.82, 1.59) RT 0.704 0.001 0.200 Yes vs. no0.95(0.71, 1.26) 0.55(0.40, 0.77) 0.82(0.60, 1.11) Abbreviations: HR, hazard ratio; CI, confidence interval; OS, overall survival; LR, local recurrence; DM, distant metastases; WD: well differentiated; DD: dedifferentiated; SFT, solitary fibrous tumor; MPNST, malignant peripheral nerve sheath tumor; RT, radiation therapy; CT, chemotherapy. * The two values are, respectively, the 3 rd and 1 st quartiles of the variable distribution.

22. Should the strategy be tailored to histology subtype? Extended resection and/or radiation for GII-GIII DD LPS? Adjacent uninvolved organ preservation in LMS and SFT? WD LPS ?

23. A closer look at outcome by center specific center was not significant on multivariate analysis but some differences in strategy and outcomes were observed

24. 1007 consecutive primary adult- type RPS from 8 centers 25% 14 % 10 % 12 % 14 %

25. 1. Focus on WD Liposarcoma Pure ALT Sclerosing, inflammatory, myxoid like, cellular (GI DD)

26. 1. Focus on WD Liposarcoma tumor size by centernumber of resected organs by center Abbreviations: IQR, interquartile range 5 (IQR 3-7) 3 (IQR 2-5) 2 (IQR 1-3) Abbreviations: IQR, interquartile range 26cm (IQR 14-24cm) 26cm (IQR 19-32cm) 24cm (IQR 16-33cm)

27. 1. Focus on WD Liposarcoma RT administration by center No100%86,5%28% Yes0%13,5%72% Quality of surgery by center Complete100%94%100% Incomplete0%6%0%

28. CCI of LR by center 5% 35% 50% 1. Focus on WD Liposarcoma

29. 88% 76% 88%

30. 1. Focus on WD Liposarcoma Better local control in patients treated by extended resection and RT OS apparently unaffected at 8-yr time point LR risk seems to flatten out with a combination of extended surgery and RT

31. 2. Focus on Leiomyosarcoma

32. tumor size by centernumber of resected organs by center 2. Focus on Leiomyosarcoma 4 (IQR 3-4) 3 (IQR 2-3) 1 (IQR 0-2)

33. RT administration by centerCT administration by center 2. Focus on Leiomyosarcoma No87%66%19% Yes13%34%81% No100%37%76% Yes0%63%24%

34. CCI of LR by centerCCI of DM by center 2. Focus on Leiomyosarcoma CCI of LR at 5yr 7,4%9,1%0% CCI of DM at 5yr 38,9%58,9%55,9%

35. 2. Focus on Leiomyosarcoma Optimal local control with adequate surgery + RT New therapies eagerly needed to address the systemic risk, as available ones seems not to help

36. Limitations Retrospective study Different case mix, different FU schedules No prospective QoL measures Similar surgical strategies, but different indication to adjuvant/neoadjuvant therapies

37. …in brief

38. After primary optimal surgery histology subtype is one of the major determinant of outcome G2-G3 DD LPS – highest LR rate G3 DD LPS and LMS – highest DM rate WD LPS indolent course but constant risk over time Conventional SFT – least LR and DM rate

39. Different strategies for local therapy May lead to different outcomes in low- intermediate grade LPS

40. 125 over 256 patients recruited

41. Different strategies for local therapy May lead to different outcomes in low- intermediate grade LPS May be of limited value when the systemic risk is high (Leio, GIII DD LPS). Need new systemic agents to address the systemic risk

42. This unprecedented collaboration has led to: The collection of a large retrospective series which will serve as historical control for all future studies An open comparison of outcomes amongst participating centers, which allows to learn what are the best practice patterns at each institution. Active recruitment of the ongoing prospective randomized study on preoperative RT in RPS, which will answer to the question of the role of RT in this disease. Application for a prospective trans-atlantic registry to create a library of information to use for future therapies

43. Trans-Atlantic RPS Working Group

44. … alessandro.gronchi@istitutotumori.mi.it