MOSAIC Data Support FOLFOX- 4 Use in High-Risk Stage II Colon Cancer

BOURNEMOUTH, United Kingdom-Treatment with the FOLFOX- 4 regimen (loading dose of fluorouracil(Drug information on fluorouracil) [5-FU] followed by infusional 5-FU, leucovorin [LV], oxaliplatin(Drug information on oxaliplatin) [Eloxatin]) may be preferable to 5- FU/LV in high-risk stage II colon cancer patients, investigators for a retrospective multi-country study have concluded (abstract 3619). The European-Israeli study is a prespecified subgroup analysis of MOSAIC (Multicenter International Study of Oxaliplatin/5-FU/Leucovorin in the Adjuvant Treatment of Colon Cancer), the recent randomized 2,200- patient trial that established FOLFOX- 4 as the first regimen to improve 3-year disease-free survival versus standard 5-FU/LV (N Engl J Med 350:2343- 2351, 2004). Strong DFS Benefit
While adjuvant chemotherapy for stage II colon cancer remains controversial, the MOSAIC subgroup analysis provides more evidence that such a treatment strategy is warranted. For stage II patients with at least one risk factor, disease-free survival at 3 years was 84.9% for FOLFOX-4 vs 79.8% (hazard ratio [HR] 0.72, relative risk reduction 28%). The data were strong enough to suggest FOLFOX-4 treatment for stage II patients with adverse prognostic factors, who "still derive risk reductions from the FOLFOX-4 therapy," said lead investigator Tamas Hickish, MD, of Dorset Cancer Center, Bournemouth, United Kingdom. "For clinicians, this means if they have a stage II patient with adverse prognostic factors-venous invasion, poor differentiation, or bowel obstruction, for example-they may wish to consider whether that patient should be treated with FOLFOX 4," he added. "The objective is to minimize that patient's risk of disease recurrence, and FOLFOX-4 appeared to do that." Prior Studies Conflicting
Adjuvant chemotherapy for stage II (Dukes' B2) colon cancer remains controversial, with conflicting data reported. A 1999 pooled analysis of four NSABP (National Surgical Adjuvant Bowel Project) trials, including 1,565 stage II patients, concluded that risk of death was similar for stage II and III, suggesting it is appropriate to include stage II patients in adjuvant trials. On the other hand, a 1999 pooled analysis of the IMPACT B2 (International Multicentre Pooled Analysis of B2 Colon Cancer Trials), including 1,600 stage II patients in five randomized trials, concluded there was no significant difference in absolute risk of death at 5 years for patients treated with 5-FU-based chemotherapy vs surgery alone. Favorable Benefit vs Risk
Most recently, a Mayo Clinic analysis (J Clin Oncol 22(10):1-10, 2004), including pooled data on 3,302 patients, concluded that stage II patients do derive a benefit, albeit to a lesser extent, than stage III patients. The MOSAIC trial, published around the same time as ASCO 2004, assessed adjuvant therapy in both stage II and III patients. For the entire intent- to-treat population, the probability of 3-year disease-free survival was 78.2% in the FOLFOX-4 arm, vs 72.9% in the 5-FU/LV arm (HR 0.77, 95% confidence interval, 0.65-0.91; P = .002). While MOSAIC was not powered to look at differences in recurrence between stage II and III colon cancer patients, further analysis presented at ASCO suggests adjuvant chemotherapy provided a 20% reduction in risk of recurrence for the stage II patients, compared with a 24% risk reduction seen in stage III patients (see Figures 1 and 2). That, coupled with a low incidence of major safety events "reflects the favorable benefit-risk of FOLFOX- 4 in this population," investigators wrote. The finding that high-risk stage II patients have a relative risk reduction of 28% illustrates the heterogeneity of this patient population, and suggests risk factors should be taken into account when treatment options are considered: "By stratifying on potential risk factors for relapse in this population, future studies will permit a better definition of the population," investigators said.