T Andre, E Quinaux, C Louvet, E Gamelin, O Bouche, E Achille, P Piedbois, N Tubiana-Mathieu, M Buyse...

T Andre, E Quinaux, C Louvet, E Gamelin, O Bouche, E Achille,

P Piedbois, N Tubiana-Mathieu, M Buyse and A de Gramont.

Updated results at 6 year of the GERCOR C96.1 phase III study comparing LV5FU2 to monthly 5FU-leucovorin (mFufol) as

adjuvant treatment for Dukes B2 and C colon cancer patients.

Introduction

Primary objective of this study: To detect a 8% difference in Disease Free Survival (DFS = colorectal cancer relapse, second colorectal cancer or death) at 3 years (α = 5% and β = 20%)

→ between LV5FU2 vs FUFOL (70 to 78%) and between 24 vs 36 weeks (70 to 78%) → 900 patients required, (2X2 factorial design, analysis on intention-to-treat basis

Toxicity results (1) and DFS at 3 years (2) were previously published. There were no difference in terms of 3-yr DFS between LV5FU2 and FUFOL and no difference in terms of treatment duration (24 vs 36 weeks) while tolerance favored LV5FU2

We report here the updated results for DFS and the final OS with 6 yr follow- up

1 André T et al. Semin Oncol 2001; 28, supp 1:35-40.

2 André T et al. J Clin Oncol 2003, 21:2896-903.

Double randomisation

FUFOL Group: 6 or 9 cycles (day 1 = day 28)D1 to D5, q4wdl-FOL 200 or l-FOL 100 mg/m2 15 min,

then FU 400 mg/m2 15 min (60 min if toxicity > 1) LV5FU2 Group: 12 or 18 cycles (day 1 = day 14)

D1 to D2, q2wdl-FOL 200 or l-FOL 100 mg/m2

5FU bolus 400 mg/m2 then 5FU CI 600 mg/m2)

the treatment group: FUFOL or LV5FU2 the treatment duration: 24 or 36 weeks

Study Design

5-FU infusion5-FU infusion 5-FU infusion5-FU infusion

D1D1 5-FU bolus5-FU bolus D2D2

LV LV

5-FU bolus5-FU bolus

Patient Characteristics

FUFOL

(N=453)

LV5FU2

(N=452)

24 Weeks

(N=454)

36 Weeks

(N=451)

Median age, years 59.7 60.2 59.6 60.3

Male/Female % 53/47 54/46 54/46 53/47

Stage II/ III % 43/57 43/57 43/57 43/57

Stage III > 4 N+ % 22 21 21 21

T4 4 4 4 5

Bowel obstruction % 17 17 17 18

Perforation % 8 7 9 7

Poor differentiation % 3 3 3 3

Four patients (0.4%) were ineligible but were nevertheless included in the analyses performed as intent-to-treat (2 patients with metastatic disease at inclusion in the LV5FU2 arm, 1 patient with metastatic disease at inclusion and 1 patient with low rectum cancer in the FUFOL arm).

Patients status (6 years of follow up)

FUFOL

(N=453)

LV5FU2

(N=452)

Median follow-up (years) 6.06 6.03

Total number of events ( N and %) 150 (33,1%) 148 (32,7%)

Deaths (all causes) (N and %) 104 (22,9%) 103 (22,8%)

Metastatic relapse (N and %) 129 (28,5%) 117 (25,9%)

Local relapse alone (N and %) 3 (0.7%) 7 (1.5%)

Death without relapse (N and %) 16 (3.5%) 21(4.6%)

Second colon or rectal cancer 2 (0.4%) 3 (0.7%)

Treatment effect: FUFOL vs LV5FU2All patients (N=905)

0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6

Pro

bab

ilit

y

DFS (Years)

Hazard ratio: 1.01 [0.81-1.27]Hazard ratio: 1.01 [0.81-1.27]

Patients Events 5 yearFUFOL 453 150 67.7%LV5FU2 452 148 67.2%


453 406 356 314 289 242 153 at

452 389 346 309 286 246 145 risk

0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6

Disease Free Survival



Hazard ratio: Hazard ratio: 1.02 [0.77, 1.34]1.02 [0.77, 1.34]

Overall survival

453 441 411 380 349 289 188

452 431 398 368 343 295 174

Survival (Years)

Treatment effect: FUFOL vs LV5FU2 Stage II (Dukes B2)

0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6

Pro

bab

ilit

y

DFS (Years)

Hazard ratio: Hazard ratio: 1.02 [0.64; 1.60]1.02 [0.64; 1.60]



0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6



Disease Free Survival Overall survival

Hazard ratio:Hazard ratio:0.89 [0.50; 1.60]0.89 [0.50; 1.60]

Survival (Years)

Treatment effect: FUFOL vs LV5FU2 Stage III (Dukes C)

0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6

Pro

bab

ilit

y

DFS (Years)

Hazard ratio: Hazard ratio: 1.01 [0.78; 1.31]1.01 [0.78; 1.31]




0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6



Overall Survival

Hazard ratio: Hazard ratio: 1.02 [0.75 ; 1.40]1.02 [0.75 ; 1.40]

Survival (Years)

Duration of treatment effect: 24 vs 36 WAll patients

0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6

Pro

bab

ilit

y

DFS (Years)


Patients Events 5 year24 weeks 454 151 67.6%36 weeks 451 147 67.3%



0,5

0,6

0,7

0,8

0,9

1

0 1 2 3 4 5 6




Overall survival

Survival (Years)

Survival after metastatic relapseAll patients

0

0,2

0,4

0,6

0,8

1

0 6 12 18 24 30 36 42 48 54

Pro

bab

ility

Survival (months)

Patients Events Time to relapse< 1 year 76 60 1-2 years 70 57 >=2 years 97 52

Log-Rank p=0.0497

Patients Events Time to relapse< 1 year 76 60 1-2 years 70 57 >=2 years 97 52

Log-Rank p=0.0497

The patients were classified according to the time to metastatic relapse into one of the following 3 categories (T0 = Randomization; (< 1 year, 1-2 years, >2 years; )

The statistically significant result of the test means that the time from metastatic relapse to death is longer for patients with longer time to metastatic relapse, as shown by the Kaplan-Meier estimations.

Conclusions

DFS and OS were not statistically different between treatment groups (FUFOL and LV5FU2) and treatment durations (24 vs 36 weeks).

These data confirm the value of LV5FU2, less toxic than FUFOL, as control arm in the MOSAIC study.

The 24 months median OS in patients with metastatic relapse, which reflects the

efficacy of new actives drugs (oxaliplatin and irinotecan), could prolong the follow-up time for survival analyses of OS in the adjuvant treatment of colon cancer.

Time from metastatic relapse to death is longer in patients with late metastatic relapse. For patients with metastatic relapse after adjuvant chemotherapy for colon cancer included in metastatic colorectal phase III studies, this observation suggests to stratify patients according to time to relapse.

T Andre, E Quinaux, C Louvet, E Gamelin, O Bouche, E Achille, P Piedbois, N Tubiana-Mathieu, M Buyse...

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