Irinotecan plus fluorouracil/leucovorin (IFL) verus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803)

Reviewer: Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2004

This presentation discusses an off-label use of irinotecan in the treatment of colon cancer.

Presenter: L.B. Saltz
Presenter's Affiliation: CALGB
Type of Session: Scientific


Metastatic colorectal cancer is a disease in which the natural history can be markedly altered by the application of effective chemotherapy agents. First-line therapy in patients with metastatic disease typically incorporates 5-fluorouracil-based (5-FU) chemotherapy agents.  There is an established survival advantage of irinotecan chemotherapy as a second line agent in metastatic colorectal cancer (MCRC) that has become refractory to 5-FU. Irinitecan also has demonstrated a survival advantage when employed as first line therapy in combination with either bolus or infusional 5-FU and leucovorin (LV), compared to 5-FU/LV alone. This specific phase III randomized study was launched to address if irinotecan with 5-FU and LV was superior to bolus 5-FU/LV in the adjuvant setting for resected stage III colon cancer patients.

Materials and Methods

  • Eligible patients all had stage III colorectal cancer (any T stage, N1-2, M0) with:
  •     negative proximal, distal and radial margins following curative resection.
  •     ECOG performance status 0-2
  •     no prior chemotherapy
  • 1,264 patients were randomized between 4/1999 and 4/2001
  • Randomization was to 1 of 2 arms:
  •     IFL (Irinotecan 125 mg/m2 IV over 90 minutes; 5-FU 500 mg/m2 IV bolus; LV 20 mg/m2 IV bolus) weekly x 4 every 6 weeks for 5 cycles -->  n= 635
  •     FL as per the Roswell Park regimen (5-FU 500 mg/m2; LV 500 mg/m2) weekly x 6 every 8 weeks for 4 cycles --> n=629      
  • Both arms were well-balanced for age and performance status.
  • Patients were stratified for N1 vs. N2 disease, high grade vs. low grade histology, and preoperative CEA levels < or > 5 ng/mL.
  • Majority of patients were stage T3 and N1.
  • The median number of lymph nodes sampled was 12 in the IFL arm and 13 in the Fl arm.
  • Study endpoints included overall survival (OS) and failure-free-survival (FFS).
  • Another entity called DFS was also examined; DFS censors out any early deaths, whereas FFS includes them.



  • Median follow-up was 3 years : 75% of expected deaths were reached, 95% of expected failures were reached
  • Median OS and FFS have not yet been reached at the time of this report.
  • None of the treatment endpoints were statistically significantly different between the two arms:
  •     OS, p=0.81
  •     FFS, p=0.89
  •     DFS, p=0.80
  • The following adverse effects were all statistically significantly worse in the IFL arm compared to the FL arm:
  •     grade 3-4 neutropenia (43% vs. 5%, p<0.00001)
  •     febrile neutropenia (4% vs 1%, p=0.0005)
  •     deaths during treatment (2.8% vs. 1%, p=0.008)
  • Fewer patients completed the planned therapy per protocol in the IFL arm compared to the FL arm (447 pts vs. 491 pts, p=0.002)
  • More patients withdrew from treatment for adverse effects in the IFL arm compared to the FL arm (67 pts vs. 35 pts, p=0.009)


Author's Conclusions

  • In stage III colorectal cancer patients who have undergone curative resection, there is no benefit to the use of adjuvant weekly bolus IFL over the standard Roswell Park-like regimen of bolus of FL.
  • The IFL curves track slightly below the FL curves, with no apparent trend towards separation.
  • Weekly bolus IFL has increased toxicity including a greater number of early deaths on treatment compared to the FL arm.
  • These are not preliminary findings, but are relatively mature, and even with longer follow-up, the authors feel strongly that this will remain a negative study.

Clinical/Scientific Implications

This is a well-designed, large study evaluating the role of irinotecan in adjuvant management of stage III colorectal cancer patients. Despite its promising, proven benefit in metastatic colorectal cancer patients, it does not appear that either overall or failure free survival are improved with the addition of irinotecan to 5-FU/LV treatment in stage III patients. Furthermore, the worse toxicity profile of the 3-drug regimen argues against any potential applicability of irinotecan to this patient group.

The negative results reported in this study prompt the natural question of why the IFL arm did not succeed. Is it that the drug itself does not have sufficient anti-tumor activity, or is it the specific regimen (ie; dosing, scheduling) that is inadequate? Ongoing trials employing irinotecan in regimens different from IFL (eg: irinotecan 180 mg/mon day 1, as in FOLFIRI) may help shed light on this question in the near future. Among those being eagerly awaited are the PETACC III and ACCORD-II (high-risk) trials due to be reported later this year.

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From the National Cancer Institute