PITTSBURGH-Compared to fluorouracil(Drug information on fluorouracil) (5-FU), oral tegafur(Drug information on tegafur)/uracil (UFT) provided "equivalent" survival, similar toxicity, and significant quality-of-life improvements in a large clinical trial among patients with stage II/III colorectal cancer. NSABP-Protocol C-06 Norman Wolmark, MD, chair of the National Surgical Adjuvant Breast and Bowel Project (NSABP), reported the results of NSABP Protocol C-06, which compared 5-FU/leucovorin to UFT/leucovorin in more than 1,600 patients (abstract 3508) at the 40th Annual Meeting of ASCO. Previous randomized trials have suggested that UFT offers efficacy and safety similar to what is obtained with standard first-line therapy for metastatic colorectal cancer. Interest Peaked in 1990s Interest in the use of UFT for colorectal cancer peaked in the 1990s, after presentation and publication of two randomized trials that examined this agent as a first-line treatment for metastatic disease. Both compared similar doses of UFT/leucovorin with the approved Mayo Clinic 5-FU/leucovorin regimen. Nearly 1,200 patients were enrolled in those trials (J Clin Oncol 20(11):3605-3616, 2002; J Clin Oncol 20(17):3617-3627, 2002). The hazard ratio for survival in the first trial favored 5-FU (HR = 0.96), while the hazard ratio in the second trial favored UFT (HR = 1.14). One can conclude there is very little difference in survival between the two arms," Dr. Wolmark noted. Those data were presented to the Oncology Drug Advisory Committee (ODAC), which made a unanimous recommendation that the drug be approved. However, "FDA declined to accept the recommendation," Dr. Wolmark said. Thus, it was "with a certain degree of dysphoria," said Dr. Wolmark, that he presented these results, "knowing that UFT is available for use in just about every country in the world, with the exception of the United States." Exceeds Efficacy Threshold In Protocol C-06, Dr. Wolmark and colleagues randomized patients with stage II/III colorectal cancer to receive either:

• the Roswell Park regimen of 5-FU/leucovorin, consisting of 5-FU 500 mg/m² IV bolus and leucovorin 500 mg/m² IV weekly for 6 weeks, followed by a 2-week rest period; this was repeated for three cycles; or
• UFT 300 mg/m²/d PO and leucovorin 90 mg/d PO for 28 days, followed by a 1-week rest period; this was repeated for five cycles.

Over a 2-year period ending March 1999, a total of 1,608 patients were enrolled. The primary aim of the study was to "compare the relative efficacy" of the regimens in prolonging survival, according to Dr. Wolmark. The secondary objective focused on quality of life issues. Five-year survival was 78.7% in both the UFT and 5-FU arms. By prespecified criteria, investigators determined that they would need a P value greater than .39 to consider the treatments equivalent; in fact, the P value was .88, which "certainly" exceeds the prespecified threshold, Dr. Wolmark noted. In addition, 5-year relapse-free survival was not significantly different between arms, at 76.4% for 5-FU/leucovorin and 74.5% for UFT/leucovorin (P = .62). Similarly, disease-free survival at 5 years was 68.3% for 5-FU/ leucovorin and 66.9% for UFT/leucovorin (P = .79), with "virtually superimposable" survival curves, Dr. Wolmark said. Quality of Life Outcomes Toxicities in the NSABP study were mainly gastrointestinal with both regimens. There was a "very similar" distribution of grade 3-4 adverse events, including diarrhea, vomiting, and nausea, Dr. Wolmark reported. The incidences in both treatment arms were 18% for grade 3 events and 19% for grade 4 events (see Table 1). Quality-of-life outcomes as measured by the SF-36 vitality scale, the symptom distress scale, symptom checklist, and burden of care questions favored the UFT arm. There was no difference in several other parameters, including the colon-specific FACT-C score, return to normal activity, and overall quality of life. "For those in the audience who treat patients in the United States, you need not encumber yourself with these data, or with the nuances of this presentation," Dr. Wolmark said in a somewhat tongue-in-cheek commentary on the results, "because UFT is not approved in the United States."