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15th Annual CTOS Meeting November 5–7, 2009

15th Annual CTOS Meeting November 5–7, 2009. PRELIMINARY RESULTS OF A RANDOMIZED TRIAL OF NEOADJUVANT CHEMOTHERAPY WITH METHOTREXATE (MTX), CISPLATIN (CDP), DOXORUBICIN (ADM), WITH OR WITHOUT IFOSFAMIDE (IFO) FOR NON-METASTATIC OSTEOSARCOMA OF THE EXTREMITY:

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15th Annual CTOS Meeting November 5–7, 2009

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  1. 15th Annual CTOS MeetingNovember 5–7, 2009 PRELIMINARY RESULTS OF A RANDOMIZED TRIAL OF NEOADJUVANT CHEMOTHERAPY WITH METHOTREXATE (MTX), CISPLATIN (CDP), DOXORUBICIN (ADM), WITH OR WITHOUT IFOSFAMIDE (IFO) FOR NON-METASTATIC OSTEOSARCOMA OF THE EXTREMITY: ANALYSIS OF HISTOLOGIC RESPONSE AND TOXICITY (ISRCTN1335128) S. Ferrari, G. Cefalo, A. Tamburini, A. Comandone, A Brach Del Prever, P.G. Casali, M Alberghini , E. Palmerini , A. Longhi,M. Mercuri, R. Capanna, S. Mappelli, P. Picci, G. Bacci.

  2. NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY

  3. NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY Best combination? MTX-CDP-ADM-IFO IFO added to MTX-CDP-ADM in all patients? MTX-CDP-ADM and IFO only in PR? IFO since primary chemo added to MTX-CDP-ADM? IFO alone or coupled to CDP and ADM?

  4. ISG/OS-1 AIMS • Evaluation of toxicity of two chemotherapy protocols with MTX, CDP, ADM and IFO, given according to different schemes, but same cumulative dose • Evaluation of efficacy (EFS, MFS, DFS) of two chemotherapy protocols with MTX, CDP, ADM and IFO, given according to different schemes, but same cumulative dose • Evaluation of the efficacy of high-dose IFO (15g/m2) as second-line treatment for patients relapsed after ISG/OS-1

  5. ISG/OS-1 STUDY DESIGN Arm A : MTX CDP ADM ± IFO RANDOM Arm B : MTX CDP ADM IFO STATISTICS Study power : 80% Significance : 0.05 Expected difference < 15% Sample : 246 pazienti Recruitment : 5 anni

  6. ISG/OS-1 ELIGIBILITY CRITERIA Histologic diagnosis of osteosarcoma G 3-4 Extremity location Age ≤ 40 years No metastases Normal epatic, renal, marrow functions. FE >50% No previous chemotherapy/surgery for osteosarcoma Informed consent Centralization of radiologic and histologic documentation

  7. ISG/OS-1 Arm A Preoperative chemotherapy M P/A M P/A ---------------------------------------- Surgery 0 1 4 5 8 weeks Postoperative chemotherapy A M M P A M M P A M M P M M -------------------------------------------------------------------------------------------- ≥90% 9 12 13 14 17 20 21 22 25 28 29 30 33 34 weeks A I M M P A I M M P A I M M P M M ---------------------------------------------------------------------------------------------------------------- 9 12 15 16 17 20 23 26 27 28 31 34 37 38 39 42 43 weeks < 90% M = methotrexate 12g/m2; P = cisplatin 120 mg/m2; A = Adriamycin 75 mg/m2 A* = 90 mg/m2; I = ifosfamide 10 g/m2

  8. ISG/OS-1 Arm B Preoperative chemotherapy M P/A M I/P I/A ---------------------------------------------- Surgery 0 1 4 5 8 11 weeks Postoperative chemotherapy P/A M M I/P I/A M M P/A M M I/A M M ----------------------------------------------------------------------------------------------------------------------- 12 15 16 17 20 23 24 25 28 29 30 33 34 weeks M = methotrexate 12g/m2; P = cisplatin 120 mg/m2; A = Adriamycin 70 mg/m2; I = ifosfamide 6 g/m2

  9. ISG/OS-1 Cumulative dose * 0 in GR Arm A 43 weeks Arm B 34 weeks

  10. ISG/OS-1 April 2001 December 2006 Clinical Characteristics

  11. ISG/OS-1 Clinical Characteristics

  12. ISG/OS-1 Compliance

  13. ISG/OS-1 Compliance Cumulative dose (m2)

  14. ISG/OS-1 Compliance Real /planned duration B 1,24±0,3 A 1,1±0,3 P=0.005 Received dose intensity ISG/OS-1 0.82 B 0.74±0,05 A 0.92±0,03 P=0.02

  15. ISG/OS-1 Toxicity

  16. ISG/OS-1 Toxicity CDP-ADM-IFO 1236 cycles

  17. ISG/OS-1 Toxicity CDP-ADM-IFO 1236 cycles

  18. ISG/OS-1 HDMTX 1553 courses Toxicity Arm A 54 (7.6%) Delayed clearance 118 (8%) Arm B 64 (8.2%) Nephrotoxicity 4 patients (1 requiring dialysis) Transaminases G4 353/1525 23% Mucositis >G1 35/1512 3%

  19. ISG/OS-1 Toxicity Renal failure 8/246 patients (3,2%) 1 patient required dialysis Cardiotoxicity 17/246 patients (7%) 2 Acute fatal cardiopathy 11 EF change >10% baseline. 4 clinical evidence of cardiopathy

  20. ISG/OS-1 Surgery P = 0.5 2 PD in primary chemotherapy. No surgery

  21. ISG/OS-1 Tumor necrosis A vs B: p = 0.3

  22. ISG/OS-1 Survival Overall Survival 75% A 75% B 75% Event-free Survival 62% A 65% B 58% OS: Median time 58 months (23-101)

  23. NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY ISG/OS-1 Ifosfamide + MTX-CDP-ADM given to all patients and since the primary phase resulted in a significantly higher toxicity As expected, aroud 60% of 5-year EFS and 75% 5-year OS with the four drug combination A similar probability of survival can be expected when ifosfamide is given in a selected population (poor responders to MTX CDP ADM) or in all patients added to MTX CDP ADM The use of ifosfamide since the primary phase added to MTX-CDP-ADM does not increase the rate of good histological responders compared to MTX-CDP-ADM

  24. NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY Standard chemotherapy MTX CDP ADM Surgery MTX CDP ADM± IFO Istituto Ortopedico Rizzoli, Bologna Istituto Nazionale Tumori, Milano Ospedale Meyer, Firenze OIRM, Torino Ospedale Bambin Gesù, Roma Ist. Gaslini, Genova Clinica Pediatrica, Padova Oncoematologia Pediatrica, Pisa CRO, Aviano Ortopedia Oncologica Careggi, Firenze Ortopedia Oncologica G. Pini, Milano Stefano.ferrari@ior.it

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