MAPIE vs MAP in patients with a Poor Response to pre-operative chemotherapy for newly-diagnosed osteosarcoma: Results from EURAMOS-1 CTOS 2014, Berlin 17-Oct-2014 Neyssa Marina , Sigbjørn Smeland, Stefan S Bielack, Mark Bernstein, Gordana Jovic, Jane M Hook, Mark D Krailo, Trüde Butterfass-Bahloul, Thomas Kühne, Mikael Eriksson, Lisa Teot, Hans Gelderblom, Leo Kager, Kirsten Sundby Hall, Richard Gorlick, R. Lor Randall, Pancras W Hogendoorn , Gabriele Calaminus, Matthew R Sydes, Jeremy S Whelan on behalf of the EURAMOS-1 investigators E UROPEAN O STEOSARCOMA I NTERGROUP Abstract ID: 2055690
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MAPIE vs MAP in patients with a Poor Response to pre-operative chemotherapy for newly-diagnosed osteosarcoma: Results from EURAMOS-1 CTOS 2014, Berlin.
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MAPIE vs MAP in patients with a Poor Response to pre-operative chemotherapy for newly-diagnosed osteosarcoma:
Results from EURAMOS-1
CTOS 2014, Berlin17-Oct-2014
Neyssa Marina, Sigbjørn Smeland, Stefan S Bielack, Mark Bernstein, Gordana Jovic,Jane M Hook, Mark D Krailo, Trüde Butterfass-Bahloul, Thomas Kühne, Mikael Eriksson,Lisa Teot, Hans Gelderblom, Leo Kager, Kirsten Sundby Hall, Richard Gorlick, R. Lor Randall, Pancras W Hogendoorn , Gabriele Calaminus, Matthew R Sydes, Jeremy S Whelanon behalf of the EURAMOS-1 investigators
E UROPEANO STEOSARCOMAI NTERGROUP
Abstract ID: 2055690
Design and eligibility
Biopsy-proven diagnosis of resectable osteosarcoma
REGISTER
MAP (induction)
Surgery
Histological response assessment
Poor Good
RANDOMIZE RANDOMIZE
MAP MAPIE MAP MAPifn
Registration
• Resectable high-grade osteosarcoma
• Extremity or axial
• Localized or metastatic
• Age ≤40yr
• No pretreatment for osteosarcoma
• No previous chemo for any disease
• No contraindication to treatment
• Registration & chemo ≤30day after biopsy
• Written informed consent
Design and eligibility
Biopsy-proven diagnosis of resectable osteosarcoma
REGISTER
MAP (induction)
Surgery
Histological response assessment
Poor Good
RANDOMIZE RANDOMIZE
MAP MAPIE MAP MAPifn
Registration
• Resectable high-grade osteosarcoma
• Extremity or axial
• Localized or metastatic
• Age ≤40yr
• No pretreatment for osteosarcoma
• No previous chemo for any disease
• No contraindication to treatment
• Registration & chemo ≤30day after biopsy
• Written informed consent
Design
Primary tumor
resectionRAP MM
IE M
A MM
wk 1-10 wk 11
wk 12-40
Ai M
wk 12-29
x2
AP MM A MMAP MM
AP MM IE M AP MM IE M Ai MM
MAPIE
MAP
Induction MAP
Eligibility for randomisation• Poor histological response to induction MAP
≥10% viable tumor in resected specimen
• Complete resection of primary tumor
• No progression
• Recovered from prior therapy
Poor Response
Dosing
M Methotrexate 12gm/m2
A Doxorubicin 75mg/m2
P Cisplatin 120mg/m2
I Ifosfamide 14g/m2
i ifosfamide 9g/m2
E Etoposide 500mg/m2
Outcome measures
• Primary
Event-free survival (EFS)• Local recurrence• Progression of existing metastases• New metastatic disease• Secondary malignancy• Death
• Secondary includeOverall survival (OS)Short & long-term toxicityQuality of life
Sample sizeAssumptions• 3yr EFS 45% (MAP) 55% (MAPIE)• Target HR = 0.75• Power 80%• Type I error 0.05
Targets• ≥ 378 EFS events• 693 Poor Response randomizations over 5 years ~ 2000 registrations
Randomisation• Permuted blocks• Stratification factors: data center, metastases status, site and
location of tumor on bone
Analyses• Treatment effect estimated with
1. Hazard Ratio (HR) from adjusted Cox model • Proportionality of hazards tested
Hazards not proportional
2. Restricted Mean Survival Time (RMST)• RMST measures average time event-free
up to a specified time point 5 yearsi.e. area under the curve
Rationale for releasing data now
• Analysis planned at ≥378 EFS events
• Fewer poor responders randomised (618/693)• Event rate is lower than predicted• Results unlikely to change in near future
• IDMC recommended early release and dissemination– After routine review of the data (Jun-2014)– Data released by the Trial Steering Committee
• Analysis includes 300 EFS events (median FU 4.5y)
Recruitment: Apr2005 – Nov2011
Registration2260
Confirmed Poor Responder
1059
Randomized 618
MAP310
MAPIE 308
1201 Not Poor Responder 1041 Confirmed Good Response 160 Response not reported
441 Not Randomized 208 (47%) Non-consent 102 (23%) Progression (local or distant) 51 (12%) Histology reported outside trial timelines 44 (10%) Not 2 cycles induction MAP 17 ( 4%) Other 15 ( 4%) No removal of mets/unresectable disease 4 ( 1%) Reason missing 1 (<1%) Good responder, entered PR rand (MAP)
COG; 313
COSS; 157
EOI; 115
SSG; 33
Baseline characteristicsMAP MAPIE
Age at randomisationMedian (IQR)(min-max) 15
4(11-18)- 40
15 5
(12-17)- 40
SexMaleFemale
174 136
(56%)(44%)
191 117
(62%)(38%)
Site of tumorProximal femur/humerusOther limb siteAxial/Skeletal
43 253
14
(14%)(82%)( 5%)
34 256
17
(11%)(83%)( 6%)
Primary metastases*YesNo
45265
(15%)(86%)
32274
(10%)(90%)
Total 310 308
*metastases status missing for 2 patients on MAPIE arm
Cumulative standardised dose
Median (IQR)Target MAP MAPIE
Number of courses
% Received targetTarget MAP MAPIE
M methotrexate (g/m2)
96 8
A doxorubicin (mg/m2)
300 4
P cisplatin (mg/m2)
240 2
I ifosfamide 14g(g/m2)
52 3
i ifosfamide 9g(g/m2)
18 2
E etoposide(g/m2)
1.5 3
Postoperative chemotherapyreceived doses
Cumulative standardised dose
Median (IQR)Target MAP MAPIE
Number of courses
% Received targetTarget MAP MAPIE
M methotrexate (g/m2)
96 94 (80-97)
88(68-97)
8
A doxorubicin (mg/m2)
300 296 (284-303)
299(233-305)
4
P cisplatin (mg/m2)
240 239(235-241)
240(230-244)
2
I ifosfamide 14g(g/m2)
52 n/a 41 (27-42)
3
i ifosfamide 9g(g/m2)
18 n/a 17 (9-18)
2
E etoposide(g/m2)
1.5 n/a 1.5 (1.0-1.5)
3
Postoperative chemotherapyreceived doses
Cumulative standardised dose
Median (IQR)Target MAP MAPIE
Number of courses
% Received targetTarget MAP MAPIE
M methotrexate (g/m2)
96 94 (80-97)
88(68-97)
8 73% 58%
A doxorubicin (mg/m2)
300 296 (284-303)
299(233-305)
4 83% 78%
P cisplatin (mg/m2)
240 239(235-241)
240(230-244)
2 92% 84%
I ifosfamide 14g(g/m2)
52 n/a 41 (27-42)
3 n/a 74%
i ifosfamide 9g(g/m2)
18 n/a 17 (9-18)
2 n/a 64%
E etoposide(g/m2)
1.5 n/a 1.5 (1-1.5)
3 n/a 75%
Postoperative chemotherapyreceived doses
Worst postoperative toxicity
*neutrophils and platelets excluded
Worst toxicityGrade 3
MAPGrade 4 Grade 5 Grade 3
MAPIEGrade 4 Grade 5
Worst non-haem* postoperative
177(59%)
59(20%)
1(<1%)
172(58%)
88(30%)
1(<1%)
Overall 237 / 300 (79%) 261 / 297 (88%)
Fisher’s test p=0.004
Worst toxicity(includes all toxicities)
Grade 3MAP
Grade 4 Grade 5 Grade 3MAPIE
Grade 4 Grade 5
Worst postoperativetoxicity
26 (9%) 259(86%)
1(<1%)
20(7%)
259(87%)
1(<1%)
Overall 286 / 300 (95%) 280 / 297 (94%)
Fisher’s test p=0.585
137
181
11
35
0
50
100
150
200
Num
ber
of
patients
3 4toxicity grade
Febrile neutropenia
MAP MAPIE
48
57
1
9
1
0
20
40
60
Num
ber
of
patients
3 4 5toxicity grade
Infection normal ANC
MAP MAPIE
103
135
4
23
0
50
100
150
Num
ber
of
patients
3 4toxicity grade
Infection documented clinically
MAP MAPIE
39
58
4
13
0
20
40
60
Num
ber
of
patients
3 4toxicity grade
Hypophosphataemia
MAP MAPIE
2
5
1
2
0
1
2
3
4
5
Num
ber
of
patients
3 4toxicity grade
Creatinine
MAP MAPIE
2
4
0
1
2
3
4
Nu
mb
er
of
pa
tient
s
3toxicity grade
Typhlitis
MAP MAPIE
Secondary malignancies (SMN)
MAP (310 pts)
MAPIE (308 pts)
Number of SMNs 2 (0.6%) Between 7 (2.3%) and 9 (2.9%)