Small But Significant Survival Advantage for Dukes’ B Patients on FUFA Regimen

BIRMINGHAM, United Kingdom- In Dukes, B colon cancer, adjuvant chemotherapy based on fluorouracil(Drug information on fluorouracil) (5-FU) provides a small but worthwhile survival advantage over observation, according to the latest analysis of data in the international QUASAR (Quick and Simple and Reliable) study (abstract 3501). The analysis involved 3,239 patients with an "uncertain" indication for chemotherapy (primarily stage II/Dukes' B disease) who were randomized to 5-FU/ folinic acid (FUFA) or observation. Survival with FUFA was three to four percentage points higher than in the observation arm. "I think it is beyond a reasonable doubt now that there is a small but definite survival benefit for Dukes' stage B patients," said Ri- chard G. Gray, MS, University of Birmingham, United Kingdom. Chemotherapy was "inexpensive" at about $4,000 per patient, and well tolerated, with no treatment-related deaths among patients who chose to have chemotherapy. Because of that, investigators believe the benefits of chemotherapy outweigh the inconvenience and cost-at least up to 70 years of age, at which point the health economics become less favorable, investigators determined. Preventing Recurrences
Prof. Gray presented results on behalf of the QUASAR Collaborative Group, which includes 322 clinicians from 150 centers in 17 countries. As part of QUASAR, patients with complete resection but an "uncertain indication" for chemotherapy were randomized to FUFA (n = 1,622) or observation (n = 1,617) The main factor leading to uncertainty about the indication for chemotherapy was node negativity due to stage II/Dukes' B colorectal cancer (92% of patients). For all patients in this study, median age was 63 years, and 71% had colon cancer. Median follow-up at the time of the analysis was 4.6 years. Chemotherapy reduced the risk of recurrence, Prof. Gray said. The 5-year recurrence was "not terribly different but highly significant" favoring chemotherapy, 22.2% vs 26.2% in the observation arms (relative risk [RR] 0.78, P < .001). The difference persisted out to almost 10 years. "All the benefit was in the first 2 years, and there was no loss of benefit or further gain," said Prof. Gray. "This is very encouraging. It means we are preventing recurrences, not just delaying them." Difference in survival at 5 years was "statistically significant but quite small," 80.3% for FUFA vs 77.4% in the observation group. This nearly 3% difference in survival translated into a reduction in risk of death of about 17%, according to the analysis (RR 0.83). For the 92% of patients with Stage II/Dukes' B disease, the difference in 5-year survival was significant, with a P value equal to .04. (Specific 5-year survival percentages for FUFA vs ob servation were not reported. "This is the first study ever to report a statistically significant benefit in Dukes' B patients" for the FUFA regimen, Prof. Gray noted. 'Highly Tolerable'
Among the more than 1,600 patients who received treatment, there were no chemotherapy-related deaths, suggesting the FUFA regimen used was "really very highly tolerable," Prof. Gray said. The QUASAR study evaluated intravenous fluorouracil (370 mg/m²) oband folinic acid, given according to a variety of schedules (six 5-day, fourweekly, or 30 once-weekly courses), with either high- or low dose folinic acid (175 or 25 mg) and with or without levamisole(Drug information on levamisole) (Ergamisol). Investigators have found that the varying schedules, varying folinic acid doses, and assignment to levamisole or placebo had no effect on recurrence rate for patients in QUASAR (Lancet 355(9215):1588-1596, 2000; Ann Oncol 947-955, 2000). 'Peculiar' Finding
One "peculiar" finding was the apparent effect of age on outcomes, contrary to some other reported studies, Prof. Gray said. While reduction in recurrence was similar in younger cohorts (up to 69 years), there appeared to be "less or no benefit" from chemotherapy in patients 70 years or older. In addition, a health economics analysis showed that the life-years gained with chemotherapy, adjusted for quality of life on chemotherapy, "becomes quite a bit less" at age 70, in part simply because older patients have fewer life-years left to gain. Assuming 1 year on chemotherapy is worth 70% of a normal year, the net gain for a 40-year-old is 2 years, while the gain for a 70-year-old patient was about 6 months, according to the analysis (see Figure 1). 'Up to 70 years of age, I think there is good evidence of benefit, but after that, it's a bit more dubious, especially given our finding of less benefit (in recurrence rate) for the over-70s," Prof. Gray stated.