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R. D. Issels, L.Lindner, Munich, Germany P. Hohenberger, Berlin/Mannheim, Germany

13th Annual CTOS Meeting. 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).

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R. D. Issels, L.Lindner, Munich, Germany P. Hohenberger, Berlin/Mannheim, Germany

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

  2. Treatment options for locally advanced sarcoma High grade: multimodal therapy • Chemotherapy (systemic) • TNF limb perfusion • Preop. Radio-(+C) therapy • Chemotherapy + RHTdeep-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 1 2 3 4

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

  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

  6. b a

  7. b a

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

  9. Patient characteristics (1)

  10. Patient characteristics (2)

  11. Patient characteristics (3)

  12. Preoperative chemotherapy

  13. Local treatment after chemotherapy

  14. WHO objective response evaluation (96% response review) * p<0.001 • 117 pts notevaluable for response (61 pts with EIA+ RHT / 56 pts with EIA)

  15. N=341 50.4% 49.6% 16.2 29.9 Median Treatment Arm n=172 n=169 88 110 Events EIA+RHT EIA 120 0 0 months 108 2 1 96 4 3 84 13 7 Disease Free Survival (All Progressions or Death) EORTC 62961/ESHO RHT 95-Study 72 13 17 rhtsur2.sas IBE 20SEP2007:12:11:53 60 24 20 Log-Rank: p=0.0034 48 27 34 36 35 44 24 50 68 12 88 114 Patients at Risk 0 172 169 0 10 90 80 70 60 50 40 30 20 100 Fig. 1 % Disease Free Survival (Any Progression or Death) 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 Cox hazard ratio = 0.66 CI95 = 0.50-0.88, p = 0.004

  16. N=341 50.4% 49.6% 26.2 37.7 Median Treatment Arm n=172 n=169 95 79 Events EIA+RHT EIA 120 0 0 months 108 2 1 96 4 4 84 14 8 Local Progression Free Survival (Local Progression or Death) EORTC 62961/ESHO RHT 95-Study 72 17 20 rhtsur2.sas IBE 20SEP2007:12:11:53 60 29 24 Log-Rank: p=0.0226 48 34 41 36 45 54 24 63 82 12 99 125 Patients at Risk 0 172 169 0 10 90 80 70 60 50 40 30 20 100 Fig. 2 % Local Progression Free Survival (Local Progression or Death) 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 Cox hazard ratio = 0.68 CI95 = 0.50-0.93, p=0.014

  17. Early Progression* S1 = primary tumor ≥5 cm, GII/GIII S2 = local recurrence of S1 tumor S3 = inadequate surgery of S1 or S2 tumor * local progression or death of any reason

  18. N=199 51.3% 48.7% 19.5 29.3 Median Treatment Arm n=102 57 55 n=97 Events EIA+RHT EIA 120 0 0 months 108 1 1 96 2 2 84 4 9 Subgroup S1/S2 Local Progression Free Survival (Local Progression or Death) EORTC 62961/ESHO RHT 95-Study 72 9 9 rhtsur2.sas IBE 20SEP2007:12:11:53 60 17 10 Log-Rank: p=0.4333 48 20 19 36 26 28 24 34 42 12 57 69 Patients at Risk 0 97 102 0 10 90 80 70 60 50 40 30 20 100 Fig. 4 % Local Progression Free Survival (Local Progression or Death) S1 + S2 - Subgroup 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

  19. N=142 49.3% 50.7% 30.0 Median - Treatment Arm 38 24 n=70 n=72 Events EIA+RHT EIA 120 0 months 108 1 0 96 2 2 84 4 5 Subgroup S3 Local Progression Free Survival (Local Progression or Death) EORTC 62961/ESHO RHT 95-Study 72 11 8 rhtsur2.sas IBE 20SEP2007:12:11:53 60 12 14 Log-Rank: p=0.0053 48 14 22 36 19 26 24 29 40 12 42 56 Patients at Risk 0 70 72 0 10 90 80 70 60 50 40 30 20 100 Fig. 5 % Local Progression Free Survival (Local Progression or Death) S3-Subgroup 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%

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

  21. Influence on Progression* (Cox model) *local progression or death

  22. ESHO National Research Center for Environment and Health Conclusions For patients with locally advanced high-grade STSregional 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

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