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 (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.
NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY
IOR/OS-2
1986-89
HDMTX-CDP-ADM±IFO
10 year DFS 63%
SSG II
1982-89
80
HDMTX-BCD±CDP-ADM
5 year DFS 54%
COSS-86
60
1986-1990
HDMTX-CDP-ADM-IFO
10 year EFS 66%
EOI
40
1983-86
CDP-ADM
5 year PFS 44%
20
CCG-782
1983-1986
HDMTX-V-BCD-ADM±CDP
8 year EFS 53%
100
0
Surgery
S+CDP/ADM
s+MTX CDP ADM IFO
FSPO Chemotherapy
HDMTX-CDP-ADM-IFO-VDS
5 year DFS
64%
%DFS
1989-1993
CCG/POG
1993-1997
HDMTX-CDP-ADM-IFO+MTP 5 year EFS 71%
ISG/SSG I
1997-2000
HDMTX-CDP-ADM-HDIFO
5 year EFS 64%
NON METASTATIC HIGH-GRADE OSTEOSARCOMA
OF THE EXTREMITY
MTX-CDP-ADM-IFO
Best combination?
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?
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 secondline treatment for patients relapsed after ISG/OS-1
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
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
ISG/OS-1
Preoperative chemotherapy
Arm A
M P/A M P/A
---------------------------------------0
1
4
5
Surgery
8
weeks
Postoperative chemotherapy
A MMP A MMP A MMP MM
≥90%
-------------------------------------------------------------------------------------------9
12 13
14
17
20 21 22
25
28 29 30
33 34 weeks
A I MMP A I MMP A I MMP M M
< 90%
---------------------------------------------------------------------------------------------------------------9
12 15 16 17
20 23 26 27 28 31 34 37 38 39
42 43 weeks
M = methotrexate 12g/m2; P = cisplatin 120 mg/m2;
A = Adriamycin 75 mg/m2 A* = 90 mg/m2; I = ifosfamide 10 g/m2
ISG/OS-1
Arm B
Preoperative chemotherapy
M P/A M I/P I/A
---------------------------------------------0
1
4
5
8
Surgery
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
ISG/OS-1
Cumulative dose
ARM A
ARM B
MTX
120 g
120 g
CDP
600 mg
600 mg
ADM
420 mg
420 mg
IFO
30 g*
30 g
Arm A
43 weeks
* 0 in GR
Arm B
34 weeks
ISG/OS-1
Clinical Characteristics
Age
Median
April 2001
December 2006
All
A
B
246
123 (50%)
123 (50%)
14
(4-39)
14
(6-39)
14
(4-34)
p
Sex
M
F
146 (59%)
100 (41%)
74 (60%)
49 (40%)
72 (59%)
51 (41%)
0.8
Site
Femur
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
ISG/OS-1
SAP
209 pz
LDH
198 pz
Clinical Characteristics
All
A
B
p
Normal
High
125 (60%)
84 (40%)
65 (62,5%)
39 (37,5%)
60 (57%)
45 (43%)
0.3
Normal
High
136 (69%)
62 (31%)
72 (72%)
28 (28%)
64 (65%)
34 (35%)
0.2
157 (64%)
24 (10%)
23 (9%)
23 (9%)
19 (8%)
76 (62%)
12 (10%)
11 (9%)
10 (8%)
16 (13%)
81 (66%)
12 (10%)
12 (10%)
9 (7%)
9 (7%)
0.5
Histology Osteoblastic
Chondroblastic
Fibroblastic
Teleangiectatic
NAS
ISG/OS-1
Compliance
Courses
3,134
A
B
1,569 (50%)
1,565 (50%)
Delayed
48,5%
Median delay
5 days
(1-40)
ISG/OS-1
Cumulative dose (m2)
Compliance
All
A
B
Planned
Dose
MTX
Median
(Min-Max)
115,5
(44-132)
115,4
(44-132)
115
(60-122)
120 g/m2
CDP
Median
(Min-Max)
589
(237-616)
590
(237-613)
588
(467-616)
600 mg/m2
ADM
Median
(Min-Max)
413
(327-440)
410
(327-422)
415
(344-440)
420 mg/m2
IFO
Median
(Min-Max)
29
(20-36)
30
(20-31)
29
(21-36)
30 g/m2
ISG/OS-1
Real /planned duration
A
1,1±0,3
P=0.005
Compliance
B
1,24±0,3
Received dose intensity
ISG/OS-1
0.82
A
0.92±0,03
P=0.02
B
0.74±0,05
ISG/OS-1
Toxicity
Disseminated intravascular coagulation
Fatal cardiopathy
Stevens-Johnson syndrome
1B
2 A-B
1B
ISG/OS-1
CDP-ADM-IFO
1236 cycles
Toxicity
26
15,5
WBC G4
PLT G4
Hospital
Febrile Neu
CSFs
Transf PLT
Transf RBC
13
20
%
67,5
15,5
22,5
0
20
40
60
80
ISG/OS-1
CDP-ADM-IFO
1236 cycles
Toxicity
80
70
A
PR only
A
110160
(28%)
(24%)
43 (11%)
93 (14%)
54 (10.5%)
84 (13%)
27 (5%)
39 (6%)
60
WBC
G4
WBC
G4
50
PLT
G4
PLT
G4
40
RBC
Transf
RBC
Transf
PLT
Transf
PLT
Transf
30
B
p
B
p
Transf RBC
336
<0.0001
336(58%)
(58%)
<0.0001
Transf
PLT
231
<0.0001
231(40%)
(40%) CSFs
<0.0001
206
<0.0001
206(33%)
(33%) Febrile
<0.0001
Neu
159
<0.0001
159(26%)
(26%) Hospital
<0.0001
CSFs
339412
(66%)
<0.002
CSFs
(63%) 422
422(73%)
(73%) PLT
<0.002
G4
20
Febrile
Neutropenia
<0.002
Febrile
Neutropenia 86 (16.5%)
109 (16%) 145
145(24%)
(24%) WBC
<0.002
G4
10
Hospitalization
39 (7.7%)
<0.0001
Hospitalization
48 (7%) 118
118(19%)
(19%)
<0.0001
0
A
B
ISG/OS-1
HDMTX
1553 courses
Toxicity
Arm A
54 (7.6%)
Delayed clearance
118 (8%)
Nephrotoxicity
4 patients
(1 requiring dialysis)
Arm B
64 (8.2%)
Transaminases G4
353/1525
23%
Mucositis >G1
35/1512
3%
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
ISG/OS-1
Surgery
Resection
Amputation
Rotation plasty
100
230 (94%)
12 (5%)
2 (1%)
96
92
90
80
Margins
70
Tot
A
B
204 (95%)
93%
96%
11 (5%)
7%
4%
60
Adequate
50
40
Inadequate
30
20
10
0
% Resection
Arm A
Arm B
P = 0.5
2 PD in primary chemotherapy. No surgery
ISG/OS-1
Tumor
necrosis
A+B
≥ 90%
45%
< 90%
55%
100
90
80
70
60
50
48
42
40
30
20
10
0
% GR
Arm A
Arm B
A vs B: p = 0.3
ISG/OS-1
Survival
1
1
,8
,8
Cum. Survival
Cum. Survival
Overall Survival
75%
,6
,4
,4
,2
,2
0
0
0
12
24
36
48
60 72
Months
84
96
A 75%
B 75%
,6
108 120
0
12
24
36
48
60 72
Months
84
96
108 120
1
1
,8
,8
,6
Cum. Survival
Cum. Survival
Event-free Survival
62%
,4
,6
,2
,2
0
0
0
12
24
36
48
60 72
Months
84
96
108 120
OS: Median time 58 months (23-101)
A 65%
B 58%
,4
0
12
24
36
48
60 72
Months
84
96
108 120
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
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