1. EARLY PROGRESSION IN PATIENTS WITH HIGH-RISK SOFT TISSUE SARCOMAS AN ANALYSIS FROM A PHASE III RANDOMIZED PROSPECTIVE TRIAL (EORTC 62961/ESHO) OF NEOADJUVANT CHEMOTHERAPY WITH OR WITHOUT REGIONAL HYPERTHERMIA (RHT) R. D. Issels, L.Lindner, Munich, Germany P. Hohenberger, Berlin/Mannheim, Germany 13th Annual CTOS Meeting

2. Treatment options for locally advanced sarcoma High grade: multimodal therapy Chemotherapy (systemic) TNF limb perfusion Preop. Radio-(+C) therapy Chemotherapy + RHT deep-wave hyperthermia

3. Application of EIA with RHT Etoposide 125 [mg/m²] Ifosfamide 1500 [mg/m²] Adriamycin 50 [mg/m²] Hyperthermia (RHT) 60 min [40°C-43°C] Day 1234

4. R A D I A T I O N Arm A Arm B EIA RHT R R A D I A T I O N Arm A Arm B EIA RHT R Study design Risk groups Stratification: Center, Risk Group, Extremity, Non-Extremity S U R G E R Y S U R G E R Y S1 = primary tumor ≥5 cm, G2/G3 S2 = local recurrence of S1 tumor S3 = inadequate surgery of S1 or S2 tumor

5. Regional Hyperthermia (RHT) Technology Courtesy of BSD Medical Corporation model BSD 2000 3D ESHO quality assurance guidelines for regional hyperthermia Lagendijk et al. Int J Hyperthermia 1998

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10. Study objectives Primary Endpoint Local Progression Free Survival (LPFS) Secondary Endpoints Tumor response (WHO) Disease Free Survival (DFS) Overall Survival

11. Patient characteristics (1) n=341EIA + RHT (n=169)EIA (n=172)p Sex Male95 (56%)94 (55%)NS Female74 (44%)78 (45%) Age 18 – 39 years41 (24%)43 (25%)NS 40 – 70 years128 (76%)129 (75%) Performance (WHO) 0108 (65%)115 (67%)NS 151 (31%)50 (29%) 28 (4%)7 (4%)

12. Patient characteristics (2) n=341EIA + RHT (n=169)EIA (n=172)p Site of tumor Extremity73 (43%)76 (44%)NS Non-Extremity96 (57%)96 (56%) Risk groups S1 (primary)78 (46%)84 (49%)NS S2 (recurrence)19 (11%)18 (10%) S3 (inadequate surgery)72 (43%)70 (41%)

13. Patient characteristics (3) n=341EIA + RHT (n=169)EIA (n=172)p Size of tumor (cm) 5-859 (35%)60 (35%)NS 9-1238 (22%)48 (28%) > 1272 (43%)64 (37%) Median11 NS Grading G284 (50%)77 (45%)NS G384 (50%)94 (55%)

14. Preoperative chemotherapy n=341 EIA + RHT (n=169)EIA (n=172)p Cycles 1-4 Received 4 cycles 150 (89%)140 (82%)NS Received ≤ 3 cycles 15 (9%) 23 (13%) Received 0 cycles 4 (2%) 9 (5%)

15. Local treatment after chemotherapy n=341 EIA + RHT (n=169)EIA (n=172)p Surgery Yes 100 (59%)101 (59%)NS No 67 (40%) 67 (39%)NS Not operated/ S3 group5553 No data2 (1%) 4 (2%)NS Radiotherapy Yes103 (61%)100 (58%)NS No 64 (38%) 66 (38%) No data 2 (1%) 6 (4%)

16. WHO objective response evaluation (96% response review) 117 pts notevaluable for response (61 pts with EIA+ RHT / 56 pts with EIA) Responder EIA + RHT (n=108) EIA (n=116) Total (n=224) CR/PR 37 (34.3%)*18 (15.5%)* 55 (24,6%) SD 63 (58.3%)71 (61,2%)134 (59,8%) PD 8 (7,4%)27 (23,3%)35 (15,6%) * p<0.001

17. Disease Free Survival (Any Progression or Death) Cox hazard ratio = 0.66 CI95 = 0.50-0.88, p = 0.004 After 3 months: 94.0% vs. 83.2% Diff. 10.8%, CI95=4.1-17.5%, p=0.002 After 6 months: 87.9% vs. 74.1% Diff. 13.8%, CI95=5.5-22.1%, p<0.001

18. Local Progression Free Survival (Local Progression or Death) Cox hazard ratio = 0.68 CI95 = 0.50-0.93, p=0.014 After 3 months: 94.6% vs. 86.2% Diff. 8.4%, CI95=2.2-14.7%, p=0.008 After 6 months: 91.6% vs. 78.2% Diff. 13.4%, CI95=5.7-20.9%, p<0.001

19. Early Progression* Treatment Time PointS1 + S2 S3 EIA + RHTat 3 months9/97 (9%)0/72 (0%) at 6 months14/97 (14%)0/72 (0%) EIAat 3 months18/102 (18%) 5/70 (7%) at 6 months25/102 (25%) 11/70 (16%) N = 199N = 142 * local progression or death of any reason S1 = primary tumor ≥5 cm, GII/GIII S2 = local recurrence of S1 tumor S3 = inadequate surgery of S1 or S2 tumor

20. Local Progression Free Survival (Local Progression or Death) After 3 months: 90.6% vs. 81.5% Diff. 9.1%, CI95=0.5-18.7%, p=0.065 After 6 months: 85.4% vs. 74.2% Diff. 11.3%, CI95=0,0-22.5%, p=0.049 S1 + S2 - Subgroup

21. Local Progression Free Survival (Local Progression or Death) After 3 months: 100% vs. 92.8% Diff. 7.2%, CI95=1.1-13.4% After 6 months: 100% vs. 84.0% Diff. 16.0%, CI95=7.3-24.6% S3-Subgroup

22. Cumulative Incidence Analysis P=0.03 NS EIA + RHT EIA Death Local Progression EIA EIA+RHT Distant Progression EIA + RHT EIA NS

23. Influence on Progression* (Cox model) P-ValueHazard- Ratio Non-Extremity<0.012.0 Tumor Size<0.011.8 Tumor Grade<0.011.5 AgeNS SexNS *local progression or death

24. Conclusions For patients with locally advanced high-grade STS regional hyperthermia + chemotherapy leads to a statistically significant improvement in: Tumor response rate Disease-free survival (DFS) Local progression-free survival (LPFS) Chemotherapy combined with hyperthermia lowers the risk of early PD for all patients - irrespective of the time point of surgery Patients receiving chemotherapy + hyperthermia after inadequate surgery seem to profit most National Research Center for Environment and Health ESHO