Oxaliplatin/5-FU/LV in Adjuvant Colon Cancer: Updated Efficacy Results of the Mosaic Trial,
Including Survival, with a Median Follow-up of 6 Years
Aimery de Gramont, Corrado Boni, Matilde Navarro, Josep Tabernero, Tamas Hickish, Clare Topham, Andrea Bonetti, Philip Clingan, Christelle Lorenzato, Thierry André, and
MOSAIC investigators
Aimery de Gramont
MOSAIC: Study Design
Primary end-point: disease-free survivalSecondary end-points: safety, overall survival
n=2246
Enrollment:Oct 1998–Jan 2001 (146 centres; 20 countries)
• Completely resected colon cancer
• Stage II, 40%; Stage III, 60%
• Age 18–75 years
• KPS ≥60
• No prior chemotherapy
RLV5FU2
FOLFOX4(LV5FU2 + oxaliplatin 85 mg/m²)
(n=1123)
(n=1123)
LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1
Cut-off Dates for Efficacy Analyses
2003 3-year DFS: primary endpoint 1
2006 5-year DFS: final update (No further updates on relapses)
2007 Overall Survival: 6-year, final analysis
1. André, et al. N Engl J Med 2004;350:2343–2351
Primary End-Point: Disease-Free Survival
• “DFS allows to make more quickly a decision regarding the efficacy of a new treatment
• Clinical trials can be completed more quickly• Drug development time can be shortened• Better therapy can be made available to patients
more quickly• DFS can be considered as an endpoint of its
own merit in decreasing the high cost, quality-of life impact and debilitating consequence of recurrent disease”
1. Sargent, et al. J Clin Oncol 2005;23:8664–8670
3 Year DFS vs 5 Year OS
0,5
0,55
0,6
0,65
0,7
0,75
0,8
0,5 0,55 0,6 0,65 0,7 0,75 0,8
5 Year OS
3 Ye
arD
FS
r=0,88
Sargent, et al. J Clin Oncol 2005;23:8664–8670
3 years
(April 20031)
5 years
(June 2006)
FOLFOX4 LV5FU2 FOLFOX4 LV5FU2
Median follow-up, months 37.9 37.8 73.5 73.4
Events (%) 21.1 26.1 27.1 32.1
DFS (%) 78.2 72.9 73.3 67.4
HR
[95% CI]
0.77
[0.65–0.91]
0.80
[0.68–0.93]
p-value 0.002 0.003
1. Andre, et al. N Engl J Med 2004;350:2343–2351
Disease-free Survival
Events = Relapse + Second Primary Colon Cancer + Death any cause
Disease-free Survival: ITT
Data cut-off: June 2006Disease-free survival (months)
FOLFOX4LV5FU2
Prob
abili
ty
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54
Events
FOLFOX4 304/1123 (27.1%)
LV5FU2 360/1123 (32.1%)
HR [95% CI]: 0.80 [0.68–0.93]
5.9%
p=0.003
Disease-free Survival: Stage II and Stage III Patients
Data cut-off: June 2006
HR [95% CI] p-value
Stage II 0.84 [0.62–1.14] 0.258
Stage III 0.78 [0.65–0.93] 0.005
FOLFOX4 stage IILV5FU2 stage IIFOLFOX4 stage IIILV5FU2 stage III
Months
Prob
abili
ty
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 72
3.8%
7.5%
p=0.258
p=0.005
Disease-free Survival: High-risk Stage II Patients
Disease-free survival (months)
FOLFOX4 n=286LV5FU2 n=290
Prob
abili
ty
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 72
3-year 5-year
FOLFOX4 85.4% 82.1%
LV5FU2 80.4% 74.9%
HR [95% CI]: 0.74 [0.52–1.06]
High-risk stage II- defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion , <10 lymph nodes examined; Data cut-off: June 2006
7.2%
Exploratory analysis
Summary: Disease-free SurvivalFinal Update
5-year DFS %
HR [95% CI] p-value FOLFOX4 LV5FU2
ITT (overall population) 73.3 67.4 0.80
[0.68–0.93]
0.003
Stage III 66.4 58.9 0.78
[0.65–0.93]
0.005
Stage II 83.7 79.9 0.84
[0.62–1.14]
0.258
High-risk stage II n=576 82.1 74.9 0.74
[0.52–1.06]
—
Low-risk stage II n=323 86.3 89.1 1.22
[0.66–2.26]
—
Data cut-off: June 2006
Secondary End-Point: Safety
NCI-CTC grade 3 (% patients) FOLFOX4 LV5FU2Neutropenia 41.0 (Gr 4, 12.2) 4.7Neutropenia with fever or infection
1.8 0.2
Diarrhea 10.8 6.7Stomatitis 2.7 2.2Vomiting 5.9 1.4Allergy 3.0 0.2Alopecia (grade 2) 5.0 5.0Neuropathy (grade 3) 12.4 0.0All cause mortality 0.5 0.5
Toxicity per Patient (on Treatment)
1. André, et al. N Engl J Med 2004;350:2343–2351
Long-term Safety
(% patients)
FOLFOX
5.3LV5FU2
5.7
0
10
20
30
40
50
60
DuringTx
6months
1-year 2-year 3-year 4-year
Grade 1Grade 2Grade 3
Data cut-off: January 2007
Second cancer
Peripheral Sensory Neuropathy
Evaluable patients n=811Grade 0 84.3%Grade 1 12.0%Grade 2 2.8%Grade 3 0.7%
Secondary End-Point: Overall Survival
FOLFOX4(n=1123)
LV5FU2(n=1123)
Number of deaths (%) 243 (21.6) 279 (24.8)Cause of death:
Adverse eventRelapseOtherMissing data
6 (0.5)189 (16.8)
44 (3.9)4 (0.4)
6 (0.5)230 (21.6)
27 (2.4)3 (0.3)
Probability of surviving (%): 3 years5 years6 years
88.281.378.6
86.679.176.0
Patients alive with recurrence (%) 69 (6.1) 88 (7.8)
Hazard ratio [95% CI] 0.85 [0.72–1.01]p-value 0.057
Data cut-off: January 2007
Overall Survival: ITT
Data cut-off: January 2007 Overall survival (months)
FOLFOX4LV5FU2
Prob
abili
ty
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90
Events
FOLFOX4 243/1123 (21.6%)
LV5FU2 279/1123 (24.8%)
HR [95% CI]: 0.85 [0.72–1.01]
2.6%
p=0.057
Overall Survival: Stage II and Stage III
Data cut-off: January 2007
FOLFOX4 stage IILV5FU2 stage IIFOLFOX4 stage IIILV5FU2 stage III
Overall survival (months)
Prob
abili
ty
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90
HR [95% CI]
Stage II 1.00 [0.71–1.42]
Stage III 0.80 [0.66–0.98]
0.1%
4.4%
p=0.996
p=0.029
Summary: Overall Survival
Probability of surviving
at 6 years, %
HR [95% CI] p-value FOLFOX4 LV5FU2
ITT (overall population) 78.6 76.0 0.85
[0.72–1.01]
0.057
Stage III 73.0 68.6 0.80
[0.66–0.98]
0.029
Stage II 86.9 86.8 1.00
[0.71–1.42]
0.996
Data cut-off: January 2007
0.5 0.7 0.9 1.1 1.3 1.5
Hazard Ratio
1
Stage III
High risk Stage II
Stage II
Stage III
High risk Stage II
Stage II
Overall survival (OS)
Disease-free survival (DFS)
Hazard ratios for DFS and OS by sub groupFavours FOLFOX4 Favours LV5FU2
Deaths other than Colon Cancer
Data cut-off: January 2007
FOLFOX4 LV5FU2Total numberOther cancers
GI cancersUrologic cancers
Lung cancersBreast-Gynecologic
HematologicalOther cancers
4821 (44%)
454323
3011 (37%)
202223
Cardio-vascular 18 (37%) 11 (37%)Pneumopathy 3 2OtherUnknown
24
33
Exploratory analysis
Exploratory analysis
FOLFOX4 LV5FU2
Number of patients with relapse 258 334
Any chemotherapy (%) 189 (73.3) 257 (76.9)
Oxaliplatin-based regimen* (%) 22 (8.5) 97 (29.0)
Irinotecan-based regimen* (%) 116 (45.0) 109 (32.6)
Other, including biologics (%) 37 (14.3) 45 (13.5)
Data cut-off: June 2006
Treatment for Recurrence
* first-line
Time from Relapse to Death: ITT
Time from relapse to death (months)
Prob
abili
ty
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
FOLFOX4 n= 258 median 21 monthsLV5FU2 n=334 median 24 months
0 6 12 18 24 6030 36 42 48 54 66 8472 78
Patients alive with relapse (%)
FOLFOX4 69 (6.1)
LV5FU2 88 (7.8)
Exploratory analysis
Conclusions
For FOLFOX4 vs LV5FU2:• The DFS benefit at 3 years was maintained at 5
years• Trend showing improved DFS in ‘high-risk’ stage
II patients• Significant OS benefit in stage III patients • No increase in the rate of secondary cancers• Continued recovery from sensory neuropathy
AcknowledgmentsDr’s Abad A, Achille E, Agostara B, Albertsson M, Ales JE, Andersen OKD, André T, Anton A, Aranda E, Basser R, Beauduin M, Benavides M, Berger C, Bessel EM, Boaziz C, Bonetti A, Boni C, Boutan-Laroze A, Bridgewater J, Bruntsch U, Bumma C, Canon JL, Carlsson G, Carmichael J, Carola E, Carrato A, Cassidy J, Catane R, Cervantes A, Chauvenet L, Clarke S, Clingan P, Colin P, Colucci G, Cortes-Funes H, Craft P, Creemers GJ, Cumin I, Cunningham D, Dahl O, Davidson N, de Braud F, de Gramont A, Della-Fiorentina S, Demol J, Depisch D, Díaz-Rubio E, Dorval E, Erdkamp FLG, Facchini T, Fahlke C, Falk S, Figer A, Fillet G, Flesch M, Fountzilas G, Ganem G, Georgoulias V, Gervasio H, Glynne-Jones R, Green M, Guérin-Meyer V, Hansen J, Hawkins R, Heike M, Heikkilä R, Hendler D, Herben MG, Hickish T, Höhler T, Honhon B, Humblet Y, Isacson R, Izso J, James R, Janinis J, Janssen M, Kahan Z, Kalofonos H, Karina M, Kerger J, Landi B, Ledermann J, Lepoutre L, Lim R, Lledo G, Maartense E, Madoe V, Maigre M, Marcuello E, Marques F,Marti P, Massuti B, Mathijs R, Maughan T, Megyery E, Mejer J, Meurisse MP, Miccio-Belaiche A, Mignot L, Mineur L, Mitchell P, Monfardini S, Monfort L, Morvan F, Mousseau M, Muron T, Myint S, Nabico R, Navarro M, Noirclerc M, Nowacki M, Nylen U, Papamichael D, Pavlidis N, Piazza E, Pinotti G, Pinter T, Polus M, Raoul Y, Ridwelski K, Rinaldi Y, Rivera F, Rosenthal M, Roth A, Samantas E, Samuel L, Sanches E, Scheithauer W, Schrijvers D, Seymour M, Shani A, Simoens M, Singer J, Skosgaard T, Slancar M, Sleebom HP, Slevin M, Smit JM, Sörensen JB, Soyer P, Steger G, Steward W, Stuart NSA, Szanto J, Szucs M, Tabernero J, Topham C, Toumieux J, Tubiana-Mathieu N, Underhill C, van Deijk WA, van den Bossche L, van Eygen K, van Laethem JL, van Veelen H, Vandebroek J, Vilain C, Vindevoghel A, Wasan H, Westman G, Wilson C, Zaniboni A
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