Randomized phase III trial comparing infused irinotecan / 5-fluorouracil (5-FU)/folinic acid (IF) versus 5-FU/FA (F) in stage III colon cancer patients (pts). (PETACC 3)

Authors: E. Van Cutsem, R. Labianca, D. Hossfeld, G. Bodoky, A. Roth, E. Aranda, B. Nordlinger, S. Assadourian, K. Wang, D. Cunningham, PETACC 3


Background: Infused IF (irinotecan/5-FU/FA) regimens have improved survival in metastatic CRC. PETACC-3 is an international randomized, prospective trial of adjuvant chemotherapy with infused IF vs. F (5-FU/FA) planned to show the increased activity of IF in pts with stage III colon cancer.

Methods: Pts with stage III and II colon cancer (UICC criteria) were given IF or F for 6 mo as the LV5FU2 (de Gramont) regimen ± irinotecan (I)180 mg/m2 q2w or as the AIO regimen ± I 80 mg/m2 weekly. The primary endpoint was the comparison of disease-free survival (DFS) in stage III pts who received IF vs. F (LV5FU2 regimen), using the log-rank test. A total of 2014 stage III pts were to be randomized in order to obtain the 452 events calculated to guarantee 90% power to detect a hazard ratio 0.73 (an increase in 3 yr DFS from 70% to 77% in IF). Secondary endpoints include RFS (Relapse FS = DFS excluding second tumor types), overall survival, safety and prognostic markers. Secondary efficacy analyses include DFS and RFS in the pooled stage II/III population.

Results: Between Jan 2000 and Apr 2002, 3278 pts (stage II/III: 945/2333) were randomized. Of the stage III pts 2094 were randomized and treated with LV5FU2 ± I according to the primary endpoint. The two arms were well balanced. Median follow-up was 32 mo. The HR for DFS was 0.89 (0.77-1.03) (p = 0.107)(3 yr DFS: 62.9 vs. 59.9 % for IF vs. F) and for RFS 0.87 (0.75-1.02) (p = 0.076) (3 yr RFS: 65.1 vs 61.8 %) in stage III pts. The HR for DFS for the pooled stage II/III population was 0.87 (0.76 - 0.99) (p = 0.038). Although pts in IF experienced slightly more toxicity, the safety profile was acceptable. The 60 d mortality (0.4/0.2 %) and the mortality within 30 d of the last treatment (0.9/0.3%) were low.

Conclusions: Irinotecan increases the efficacy of LV5FU2 in stage III colon cancer pts, without reaching statistical significance at a median follow-up of 32 mo with an acceptable safety profile. Irinotecan increases significantly the efficacy of LV5FU2 in the pooled population of stage II/III patients.