15th Annual CTOS Meeting November 5–7, 2009 ESULTS OF A RANDOMIZED TRIAL OF NEOADJUVANT CHEMOTHERAPY XATE (MTX), CISPLATIN (CDP), DOXORUBICIN (ADM), UT IFOSFAMIDE (IFO) FOR NON-METASTATIC OSTEOSARCOMA OF THE EXTREMITY: ISTOLOGIC RESPONSE AND TOXICITY (ISRCTN1335128) . Cefalo, A. Tamburini, A. Comandone, A Brach Del Prever, P.G. Casali, M Alberghini , E Mercuri, R. Capanna, S. Mappelli, P. Picci, G. Bacci.
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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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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.
0
20
40
60
80
100
Chemotherapy Surgery S+CDP/ADM s+MTX CDP ADM IFO
%DFS
NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITYNON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY
IOR/OS-2 IOR/OS-2
1986-891986-89
HDMTX-CDP-ADM±IFOHDMTX-CDP-ADM±IFO 10 year DFS 63%10 year DFS 63%
SSG II SSG II
1982-891982-89
HDMTX-BCD±CDP-ADMHDMTX-BCD±CDP-ADM 5 year DFS 54%5 year DFS 54%
COSS-86 COSS-86
1986-19901986-1990
HDMTX-CDP-ADM-IFOHDMTX-CDP-ADM-IFO 10 year EFS 66%10 year EFS 66%
EOI EOI
1983-861983-86
CDP-ADMCDP-ADM 5 year PFS 44%5 year PFS 44%
CCG-782 CCG-782
1983-19861983-1986
HDMTX-V-BCD-ADM±CDPHDMTX-V-BCD-ADM±CDP 8 year EFS 53%8 year EFS 53%
FSPO FSPO
1989-19931989-1993
HDMTX-CDP-ADM-IFO-VDSHDMTX-CDP-ADM-IFO-VDS 5 year DFS 64%5 year DFS 64%
CCG/POGCCG/POG
1993-19971993-1997
HDMTX-CDP-ADM-IFO+MTPHDMTX-CDP-ADM-IFO+MTP 5 year EFS 71%5 year EFS 71%
ISG/SSG IISG/SSG I
1997-20001997-2000
HDMTX-CDP-ADM-HDIFOHDMTX-CDP-ADM-HDIFO 5 year EFS 64%5 year EFS 64%
MTX-CDP-ADM-IFOMTX-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 NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITYOF THE EXTREMITY
ISG/OS-1ISG/OS-1
AIMSAIMS
• Evaluation of toxicity of two chemotherapy protocols with MTX, Evaluation of toxicity of two chemotherapy protocols with MTX, CDP, ADM and IFO, given according to different schemes, but CDP, ADM and IFO, given according to different schemes, but same cumulative dosesame cumulative dose
• Evaluation of efficacy (EFS, MFS, DFS) of two chemotherapy Evaluation of efficacy (EFS, MFS, DFS) of two chemotherapy protocols with MTX, CDP, ADM and IFO, given according to protocols with MTX, CDP, ADM and IFO, given according to different schemes, but same cumulative dosedifferent schemes, but same cumulative dose
• Evaluation of the efficacy of high-dose IFO (15g/m2) as second-Evaluation of the efficacy of high-dose IFO (15g/m2) as second-line treatment for patients relapsed after ISG/OS-1line treatment for patients relapsed after ISG/OS-1
STUDY DESIGNSTUDY DESIGN
Arm AArm A : : MTX CDP ADM ± IFOMTX CDP ADM ± IFORANDOMRANDOM
A M M P A M M P A M M P M MA 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----------------------------------------------------------------------------------------------------------------9 12 15 16 17 20 23 26 27 28 31 34 37 38 39 42 43 weeks
P/A M M I/P I/A M M P/A M M I/A M MP/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 weeks12 15 16 17 20 23 24 25 28 29 30 33 34 weeks
2 Acute fatal cardiopathy11 EF change >10% baseline. 4 clinical evidence of cardiopathy
ToxicityToxicityISG/OS-1ISG/OS-1
92 96
0
10
20
30
40
50
60
70
80
90
100
% Resection
Arm A Arm B
2 PD in primary chemotherapy. No surgery
Resection 230 (94%)
Amputation 12 (5%)
Rotation plasty 2 (1%)
P = 0.5
SurgerySurgery
Margins Tot A B
Adequate 204 (95%) 93% 96%
Inadequate 11 (5%) 7% 4%
ISG/OS-1ISG/OS-1
A+B
≥ 90% 45%
< 90% 55%
A vs B: p = 0.3
4842
0
10
20
30
40
50
60
70
80
90
100
% GR
Arm A Arm B
Tumor Tumor necrosisnecrosis
ISG/OS-1ISG/OS-1
SurvivalSurvival
0
,2
,4
,6
,8
1
Cum
. Sur
viva
l
0 12 24 36 48 60 72 84 96 108 120Months
0
,2
,4
,6
,8
1C
um. S
urvi
val
0 12 24 36 48 60 72 84 96 108 120Months
Overall SurvivalOverall Survival
Event-free SurvivalEvent-free Survival
62%A 65%B 58%
OS: Median time 58 months (23-101)
ISG/OS-1ISG/OS-1
0
,2
,4
,6
,8
1
Cum
. Sur
viva
l
0 12 24 36 48 60 72 84 96 108 120Months
75%
0
,2
,4
,6
,8
1
Cum
. Sur
viva
l
0 12 24 36 48 60 72 84 96 108 120Months
A 75%B 75%
NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITYNON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY
ISG/OS-1ISG/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