NEW YORK - Weekly bolus IFL (irinotecan [CPT-11,Camptosar]/fluorouracil [5-FU]/leucovorin [folinic acid]) "should not be used" in the management of stage III colon cancer, according to Leonard Saltz, MD, an associate attending physician at Memorial-Sloan Kettering Cancer Center. Compared with the Roswell Park schedule of bolus 5-FU/leucovorin (FL), weekly bolus IFL had no additional clinical benefit, and it was associated with greater toxicity and more deaths on treatment, Dr. Saltz report- ed (abstract 3500) (Table 1). "These are not preliminary findings," Dr. Saltz said. "The futility boundaries have been crossed and this will not be a positive study." Route of Administration May Play Role
Positive results using IFL to treat metastatic colorectal cancer have led investigators to hypothesize that IFL also may be beneficial in the adjuvant setting. It is unclear why such a benefit was not shown, although there is some speculation that the route of 5-FU administration (bolus vs infusional) may play a role. "Why didn't it work? Was it the drug or the regimen? I don't think we know the answer yet," Dr. Saltz said. "There is certainly some evidence that adding other efficacious agents, such as oxaliplatin(Drug information on oxaliplatin) [Eloxatin], to 5-FU/leu- covorin can lead to favorable outcomes in stage III colorectal cancer." Dr. Saltz reported the results of the Cancer and Leukemia Group B (CALGB) study C89803, an intergroup trial designed to evaluate the usefulness of irinotecan(Drug information on irinotecan) when added to bolus FL after curative resection for patients with stage III colon cancer (T_anyN_1-2M₀) who have had no prior chemotherapy. Patients were randomized to receive:

• the Roswell Park FL schedule of leucovorin 500 mg/m² IV over 2 hours, plus 5-FU 500 mg/m² 1 hour after start of leucovorin, 6 weeks on, 2 weeks off for four cycles; or
• an IFL schedule of irinotecan 125 mg/m² over 90 minutes followed by leucovorin 20 mg/m² IV bolus, then 5-FU 500 mg/m² IV bolus 4 weeks on, 2 weeks off for five cycles.

'No Meaningful Differences'
Approximately 55% of patients were male and about 25% were age 70 years or older. Zubrod performance status was 0 in more than 70% of patients; the rest had a performance status of 1. Seventy-five percent had T3 disease and the majority of patients (61%) had N1 disease. With a median follow-up of 3 years, there were "no meaningful differences" in overall survival between IFL and FL (P = .81), Dr. Saltz reported. The investigational arm actually tracked "slightly below" the control arm, although not to a significant degree (see Figure 1). Similarly, failure-free survival and disease-free survival data provided no indication of improving when irinotecan was added (P values of .89 and .80, respectively). There was an excess of potentially treatment-related deaths accruing to the IFL arm, 2.8% vs 1% for FL (P = .008). While diarrhea and nausea rates were similar for IFL and FL, rates of neutropenia and febrile neutropenia were higher for IFL; the rate of febrile neutropenia was 4% for IFL vs 1% for FL (P = .0005, see Table 1). These results were somewhat unexpected. Irinotecan has proven ben- efit in second-line treatment of metastatic colorectal cancer, and as firstline therapy, irinotecan improves survival when added to bolus or infusional FL. "It seemed like a reasonable and almost slam-dunk idea," Dr. Saltz said, "that if we put irinotecan into the adjuvant setting, we would improve outcomes for our patients." There is certainly evidence that other active agents, namely oxaliplatin, can lead to favorable outcomes when added to standard therapy for stage III colorectal cancer. Last year at ASCO, De Gramont et al showed that oxaliplatin plus infusional FL (FOLFOX-4) significantly improved 3-year diseasefree survival rates vs infusional FL alone. "The question is whether this would be seen with irinotecan and infusional FL," Dr. Saltz. Other Studies Underway
There are studies underway that will address the question of irinotecan plus infusional FL in the adjuvant setting. One is PETACC III, a large, randomized trial comparing a 5-FU/ folinic acid/irinotecan (FOLFIRI) regimen with infusional FL in 800 stage II and 2,330 stage III patients. The study closed to accrual in 2002 and results are expected later this year. The phase III randomized Accord02/ FFCD9802 trial is also evaluating the FOLFIRI regimen vs infusional FL. That trial has enrolled 400 patients. Interim safety results were described at ASCO 2003 (abstract 1183) and more results are anticipated in late 2004. "We need to keep an open mind on the question of whether or not irinotecan with infusional 5-FU will be efficacious or not in stage III patients," Dr. Saltz said. "Right now, we simply don't have data."