15th Annual CTOS Meeting November 5–7, 2009 PRELIMINARY RESULTS OF A RANDOMIZED TRIAL OF NEOADJUVANT CHEMOTHERAPY WITH METHOTREXATE (MTX), CISPLATIN (CDP),

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Presentation transcript:

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: ANALYSIS OF HISTOLOGIC RESPONSE AND TOXICITY (ISRCTN ) 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.

NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY IOR/OS HDMTX-CDP-ADM±IFO 10 year DFS 63% SSG II HDMTX-BCD±CDP-ADM 5 year DFS 54% 5 year DFS 54% COSS HDMTX-CDP-ADM-IFO 10 year EFS 66% EOI CDP-ADM 5 year PFS 44% CCG HDMTX-V-BCD-ADM±CDP 8 year EFS 53% FSPO HDMTX-CDP-ADM-IFO-VDS 5 year DFS 64% CCG/POG HDMTX-CDP-ADM-IFO+MTP 5 year EFS 71% ISG/SSG I HDMTX-CDP-ADM-HDIFO 5 year EFS 64%

MTX-CDP-ADM-IFO 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? IFO added to MTX-CDP-ADM in all patients? Best combination? NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY

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 doseEvaluation 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 doseEvaluation 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-1Evaluation of the efficacy of high-dose IFO (15g/m2) as second- line treatment for patients relapsed after ISG/OS-1

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

Preoperative chemotherapy M P/A M P/A Surgery M = methotrexate 12g/m2; P = cisplatin 120 mg/m2; A = Adriamycin 75 mg/m2 A* = 90 mg/m2; I = ifosfamide 10 g/m2 Arm A Postoperative chemotherapy A M M P A M M P A M M P M M A I M M P A I M M P A I M M P M M weeks ≥90% < 90% weeks weeks ISG/OS-1

M P/A M I/P I/A Surgery weeks M = methotrexate 12g/m2; P = cisplatin 120 mg/m2; A = Adriamycin 70 mg/m2; I = ifosfamide 6 g/m2 Arm B Preoperative chemotherapy Postoperative chemotherapy P/A M M I/P I/A M M P/A M M I/A M M weeks ISG/OS-1

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

AllABp (50%) Age Median 14 (4-39) 14 (6-39) 14 (4-34) SexMFMF 146 (59%) 100 (41%) 74 (60%) 49 (40%) 72 (59%) 51 (41%) 0.8 SiteFemur Tibia Humerus Other 131 (53%) 60 (25%) 34 (14%) 21 (8%) 62 (50%) 34 (28%) 14 (11%) 13 (11%) 69 (56%) 26 (21%) 20 (16%) 8 (7%) 0.3 April 2001 December 2006 Clinical Characteristics ISG/OS-1

AllABp SAP 209 pz Normal High 125 (60%) 84 (40%) 65 (62,5%) 39 (37,5%) 60 (57%) 45 (43%) 0.3 LDH 198 pz Normal High 136 (69%) 62 (31%) 72 (72%) 28 (28%) 64 (65%) 34 (35%) 0.2 HistologyOsteoblastic Chondroblastic Fibroblastic Teleangiectatic NAS 157 (64%) 24 (10%) 23 (9%) 19 (8%) 76 (62%) 12 (10%) 11 (9%) 10 (8%) 16 (13%) 81 (66%) 12 (10%) 9 (7%) 0.5 Clinical Characteristics ISG/OS-1

Delayed48,5% Median delay5 days (1-40) AB Courses3,1341,569 (50%)1,565 (50%) ComplianceISG/OS-1

AllABPlanned Dose MTX Median (Min-Max) 115,5 (44-132) 115,4 (44-132) 115 (60-122) 120 g/m2 CDP Median (Min-Max) 589 ( ) 590 ( ) 588 ( ) 600 mg/m2 ADM Median (Min-Max) 413 ( ) 410 ( ) 415 ( ) 420 mg/m2 IFO Median (Min-Max) 29 (20-36) 30 (20-31) 29 (21-36) 30 g/m2 Cumulative dose (m2) ComplianceISG/OS-1

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

Disseminated intravascular coagulation1 B Fatal cardiopathy2 A-B Stevens-Johnson syndrome1 B ToxicityISG/OS-1

CDP-ADM-IFO 1236 cycles ToxicityISG/OS-1

CDP-ADM-IFO 1236 cycles ToxicityABp WBC G4 160 (24%) 336 (58%) < PLT G4 93 (14%) 231 (40%) < RBC Transf 84 (13%) 206 (33%) < PLT Transf 39 (6%) 159 (26%) < CSFs 412 (63%) 422 (73%) <0.002 Febrile Neutropenia 109 (16%) 145 (24%) <0.002 Hospitalization 48 (7%) 118 (19%) < A PR only Bp WBC G4 110 (28%) 336 (58%) < PLT G4 43 (11%) 231 (40%) < RBC Transf 54 (10.5%) 206 (33%) < PLT Transf 27 (5%) 159 (26%) < CSFs 339 (66%) 422 (73%) <0.002 Febrile Neutropenia 86 (16.5%) 145 (24%) <0.002 Hospitalization 39 (7.7%) 118 (19%) <0.0001ISG/OS-1

HDMTX 1553 courses Delayed clearance 118 (8%) Arm A 54 (7.6%) Arm B 64 (8.2%) Nephrotoxicity 4 patients (1 requiring dialysis) Transaminases G4 353/152523% Mucositis >G1 35/15123% ToxicityISG/OS-1

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 ToxicityISG/OS-1

2 PD in primary chemotherapy. No surgery Resection230 (94%) Amputation12 (5%) Rotation plasty2 (1%) P = 0.5 Surgery MarginsTotAB Adequate204 (95%)93%96% Inadequate11 (5%)7%4%ISG/OS-1

A+B ≥ 90%45% < 90%55% A vs B: p = 0.3 TumornecrosisISG/OS-1

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

NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY ISG/OS-1 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 Ifosfamide + MTX-CDP-ADM given to all patients and since the primary phase resulted in a significantly higher toxicity

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 Standard chemotherapy MTX CDP ADM Surgery MTX CDP ADM± IFO MTX CDP ADM Surgery MTX CDP ADM ± IFO NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY