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Aimery de gramont

Aimery de Gramont

Oxaliplatin/5-FU/LV in Adjuvant Colon Cancer: Updated Efficacy Results of the Mosaic Trial, Including Survival, with a Median Follow-up of 6 YearsAimery de Gramont, Corrado Boni, Matilde Navarro, Josep Tabernero, Tamas Hickish, Clare Topham, Andrea Bonetti, Philip Clingan, Christelle Lorenzato, Thierry André, and MOSAIC investigators


Primary end point disease free survival secondary end points safety overall survival

Primary end-point: disease-free survival

Secondary 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

(n=1123)

FOLFOX4

(LV5FU2+ oxaliplatin 85 mg/m²)

R

LV5FU2

(n=1123)

MOSAIC: Study Design

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

Cut-off Dates for Efficacy Analyses

1. André, et al. N Engl J Med 2004;350:2343–2351


Primary end point disease free survival

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


Disease free survival

Disease-free Survival

Events = Relapse + Second Primary Colon Cancer + Death any cause

1. Andre, et al. N Engl J Med 2004;350:2343–2351


Disease free survival itt

1.0

0.9

0.8

5.9%

0.7

0.6

0.5

Probability

Events

FOLFOX4 304/1123 (27.1%)

LV5FU2 360/1123 (32.1%)

HR [95% CI]: 0.80 [0.68–0.93]

0.4

FOLFOX4

LV5FU2

0.3

0.2

0.1

0

0

6

12

18

24

30

36

42

48

54

60

Disease-free survival (months)

Disease-free Survival: ITT

p=0.003

Data cut-off: June 2006


Disease free survival stage ii and stage iii patients

1.0

0.9

0.8

0.7

0.6

Probability

0.5

0.4

0.3

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

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

0.2

0.1

0

0

6

12

18

24

30

36

42

48

54

60

66

72

Months

Disease-free Survival: Stage II and Stage III Patients

p=0.258

3.8%

p=0.005

7.5%

Data cut-off: June 2006


Disease free survival high risk stage ii patients

Disease-free Survival: High-risk Stage II Patients

1.0

0.9

0.8

7.2%

0.7

FOLFOX4 n=286

LV5FU2 n=290

0.6

0.5

Probability

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

0.4

0.3

0.2

0.1

0

0

6

12

18

24

30

36

42

48

54

60

66

72

Disease-free survival (months)

Exploratory analysis


Summary disease free survival final update

Summary: Disease-free SurvivalFinal Update

Data cut-off: June 2006


Secondary end point safety

Secondary End-Point: Safety

Toxicity per Patient (on Treatment)

1. André, et al. N Engl J Med 2004;350:2343–2351


Long term safety

Long-term Safety

Second cancer

Peripheral Sensory Neuropathy

Data cut-off: January 2007


Secondary end point overall survival

Secondary End-Point: Overall Survival

Data cut-off: January 2007


Overall survival itt

FOLFOX4

LV5FU2

Overall Survival: ITT

1.0

p=0.057

0.9

0.8

2.6%

0.7

0.6

0.5

Probability

0.4

Events

FOLFOX4 243/1123 (21.6%)

LV5FU2 279/1123 (24.8%)

HR [95% CI]: 0.85 [0.72–1.01]

0.3

0.2

0.1

0

0

6

12

18

24

30

36

42

48

54

60

66

72

78

84

90

96

Overall survival (months)

Data cut-off: January 2007


Overall survival stage ii and stage iii

1.0

0.9

0.8

0.7

0.6

0.5

Probability

0.4

HR [95% CI]

Stage II 1.00 [0.71–1.42]

Stage III 0.80 [0.66–0.98]

0.3

0.2

0.1

0

0

6

12

18

24

30

36

42

48

54

60

66

72

78

84

90

96

Overall survival (months)

Overall Survival: Stage II and Stage III

p=0.996

0.1%

p=0.029

4.4%

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Data cut-off: January 2007


Summary overall survival

Summary: Overall Survival

Data cut-off: January 2007


Hazard ratios for dfs and os by sub group

Hazard ratios for DFS and OS by sub group

Favours FOLFOX4 Favours LV5FU2

Disease-free survival (DFS)

Stage II

High risk Stage II

Stage III

Overall survival (OS)

Stage II

High risk Stage II

Stage III

1

0.5

0.7

0.9

1.1

1.3

1.5

Hazard Ratio


Deaths other than colon cancer

Deaths other than Colon Cancer

Exploratory analysis

Data cut-off: January 2007


Treatment for recurrence

Treatment for Recurrence

* first-line

Exploratory analysis

Data cut-off: June 2006


Time from relapse to death itt

Time from Relapse to Death: ITT

1.0

0.9

0.8

0.7

FOLFOX4 n= 258 median 21 months

LV5FU2 n=334 median 24 months

0.6

0.5

Probability

0.4

0.3

Patients alive with relapse (%)

FOLFOX4 69 (6.1)

LV5FU2 88 (7.8)

0.2

0.1

0

0

6

12

18

24

30

36

42

48

54

60

66

72

78

84

Time from relapse to death (months)

Exploratory analysis


Conclusions

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


Acknowledgments

Acknowledgments

Dr’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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