In Colorectal Cancer, Reduced-Dose IFL Is Active, Less Toxic Than FOLFOX

CHAPEL HILL, North Carolina- In advanced colorectal cancer, reduced-dose irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) plus fluorouracil(Drug information on fluorouracil) (5-FU)/ leucovorin (LV) (IFL) can provide similar efficacy with a lower toxicity burden vs standard IFL, an analysis of the Intergroup N9741 trial has shown. Reduced-dose IFL was still not superior to FOLFOX (oxaliplatin [Eloxatin]/ 5-FU/LV), the other regimen evaluated in the N9741, the data show (abstract 3621). "FOLFOX was still superior, and significantly so, with respect to the response rate, time to progression, and survival," said investigator Richard M. Goldberg, MD, professor and chief of Hematology/ Oncology at the University of North Carolina at Chapel Hill. Nevertheless, because reduceddose IFL retains activity with more acceptable toxicity, the regimen may have utility, particularly as a platform for evaluating targeted therapies. "You can retain the activity of IFL-if you choose to use IFL-by giving lower doses, and that improves patient safety dramatically," Dr. Goldberg said. Intergroup N9741 Analysis
In the N9741 clinical trial, the dose of IFL was reduced because of increased toxicity and early mortality observed with the regimen (J Clin Oncol 19(18):3801-3807, 2001). Investigators reduced doses of both irinotecan (from 125 to 100 mg/m²) and 5- FU (from 500 to 400 mg/m²), but did not change the dose of leucovorin (20 mg/m²). Subsequently, 355 of a planned 600 patients were randomized to reduced-dose IFL or FOLFOX- 4. (Randomization was stopped early because of superior results with FOLFOX.) Investigators randomized 151 patients to the reduced-dose IFL regi- men, given weekly for 4 weeks, every 6 weeks; and 154 patients were randomized to the usual FOLFOX-4 regimen (oxaliplatin 85 mg/m² on day 1, and leucovorin 200 mg/m² on days 1 and 2, followed by a loading dose of 5-FU 400 mg/m² bolus, and then 5-FU 600 mg/m² as a 22-hour infusion on days 1 and 2, every 2 weeks). FOLFOX-4 Better
All clinical endpoints favored FOLFOX-4. Responses were seen in 47% of FOLFOX-4 patients and in 32% of reduced-dose IFL-treated patients (P = .006). With a median follow- up of 22.5 months, time to progression was 10 months vs 6 months for reduced-dose IFL (P < .0001). Median survival was 18.8 months vs 16.3 months for FOLFOX-4 and reduced- dose IFL, respectively (hazard ratio 0.76, P = .054). However, the efficacy seen with reduced- dose IFL is similar to what has been reported for the higher IFL dose. In a paper published January 2004 in the Journal of Clinical Oncology (22:4- 6), Dr. Goldberg and colleagues reported a response rate of 32%, time to progression of 6.9 months, and an overall survival time of 15 months for patients on full-dose IFL. Furthermore, the toxicity of reduced- dose IFL was similar to what was seen with FOLFOX-4. There was no significant difference in incidence of grade 3 or worse nausea, vomiting, dehydration, or diarrhea between the two regimens; FOLFOX-4 was associated with a significantly higher incidence of serious neutropenia, paresthesia and infection, although the incidence of febrile neutropenia was similar between arms (7% and 12% for reduced-dose IFL and FOLFOX-4, respectively). It was also reported at ASCO that many patients in the reduced-dose IFL arm went on to receive oxaliplatin(Drug information on oxaliplatin) in the second-line setting; likewise, many patients randomized to FOLFOX-4 went on to receive irinotecan. "The significant benefit of FOLFOX-4 over reduced-dose IFL was maintained in the presence of common usage of second- line oxaliplatin," investigators wrote in their poster presentation. This study was supported by Pharmacia, Sanofi-Synthelabo, and a grant from the National Institutes of Health.