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: André T et al. J Clin Oncol 2003, 21:

Double randomisation  FUFOL Group: 6 or 9 cycles (day 1 = day 28) D1 to D5, q4w dl-FOL 200 or l-FOL 100 mg/m 2 15 min, then FU 400 mg/m 2 15 min (60 min if toxicity > 1)  LV5FU2 Group: 12 or 18 cycles (day 1 = day 14) D1 to D2, q2w dl-FOL 200 or l-FOL 100 mg/m 2 5FU bolus 400 mg/m2 then 5FU CI 600 mg/m 2 )  the treatment group: FUFOL or LV5FU2  the treatment duration: 24 or 36 weeks Study Design 5-FU infusion D1 5-FU bolus D2 LV 5-FU bolus

Patient Characteristics FUFOL (N=453) LV5FU2 (N=452) 24 Weeks (N=454) 36 Weeks (N=451) Median age, years Male/Female % 53/4754/46 53/47 Stage II/ III % 43/57 Stage III > 4 N+ % 2221 T Bowel obstruction % Perforation % 8797 Poor differentiation % 3333 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) 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 cancer2 (0.4%)3 (0.7%)

Treatment effect: FUFOL vs LV5FU2 All patients (N=905) Probability DFS (Years) Hazard ratio: 1.01 [ ] Patients Events 5 year FUFOL % LV5FU % Patients Events 5 year FUFOL % LV5FU % at risk Disease Free Survival Patients Events 5 year FUFOL % LV5FU % Patients Events 5 year FUFOL % LV5FU % Hazard ratio: 1.02 [0.77, 1.34] Overall survival Survival (Years)

Treatment effect: FUFOL vs LV5FU2 Stage II (Dukes B2) Probability DFS (Years) Hazard ratio: 1.02 [0.64; 1.60] Patients Events 5 year FUFOL % LV5FU % Patients Events 5 year FUFOL % LV5FU % Patients Events 5 year FUFOL % LV5FU % Patients Events 5 year FUFOL % LV5FU % Disease Free Survival Overall survival Hazard ratio:0.89 [0.50; 1.60] Survival (Years)

Treatment effect: FUFOL vs LV5FU2 Stage III (Dukes C) Probability DFS (Years) Hazard ratio: 1.01 [0.78; 1.31] Patients Events 5 year FUFOL % LV5FU % Patients Events 5 year FUFOL % LV5FU % Disease Free Survival Patients Events 5 year FUFOL % LV5FU % Patients Events 5 year FUFOL % LV5FU % Overall Survival Hazard ratio: 1.02 [0.75 ; 1.40] Survival (Years)

Duration of treatment effect: 24 vs 36 W All patients Probability DFS (Years) Hazard ratio: 0.97 [ ] Patients Events 5 year 24 weeks % 36 weeks % Patients Events 5 year 24 weeks % 36 weeks % Disease Free Survival Patients Events 5 year 24 weeks % 36 weeks % Patients Events 5 year 24 weeks % 36 weeks % Hazard ratio: 1.11 [ ] Overall survival Survival (Years)

Survival after metastatic relapse All patients Probability Survival (months) Patients Events Time to relapse < 1 year years >=2 years Log-Rank p= Patients Events Time to relapse < 1 year years >=2 years Log-Rank p=  The patients were classified according to the time to metastatic relapse into one of the following 3 categories (T0 = Randomization; ( 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.