Fluorouracil, oxaliplatin and CPT-11 (irinotecan), use and sequencing (MRC FOCUS): A 2135-patient randomized trial in advanced colorectal cancer (ACRC)

Abstract

3518 Background: This multicenter, open randomized trial assesses the effect on overall survival (OS) and quality of life of the planned sequencing of the first two cytotoxic drugs (fluorouracil (FU) plus one other) received by patients (pts) with inoperable ACRC. It compares three approaches: sequential single agents (FU first then change to second drug); sequential single/combination (FU then add a second drug); or 1st-line combination. It also compares irinotecan (Ir) and oxaliplatin (Ox) combinations. Methods: Pts had PS 0–2; GFR >50; ALP <5 x ULN; bili <1.25 x ULN. Randomization was 2:1:1:1:1 to: Plan A (reference): MdG (Modified de Gramont: leucovorin; FU bolus + 48 hr infusion; q2w) until treatment failure, then 2nd-line Ir; Plans Bir and Box: MdG until treatment failure, then 2nd-line IrMdG or OxMdG respectively; Plans Cir and Cox: 1st-line IrMdG or OxMdG. Primary endpoint was OS, 2100 pts giving 80% power (α = 0.01) to detect a difference of 22.5% vs 15% in 2 yr OS of each plan against Plan A. Results: 2135 pts entered, May’00 - Dec’03, at 61 centres, median age 64 yrs; 92% PS 0–1. With 1435 deaths to date, the primary comparisons, of OS for each plan (Bir, Box, Cir, Cox) versus Plan A, show trends to improvement (HR 0.92, 0.91, 0.86, 0.96 respectively) but all are non-significant (all p > 0.05). Grouped comparison of OS in Plans B (712 pts) with Plan A (710 pts) has a HR of 0.91, 95% CI (0.81, 1.04) p=0.157 in favour of B. The comparison of OS in grouped Plans C (713 pts) with Plan A has a HR of 0.91 (0.80, 1.03) p=0.134 favouring C. Comparison of Plans B with Plans C has a HR of 1.00 (0.88, 1.14) p=0.993. OS does not differ significantly between Ox and Ir in plans B and C. Compared with Plan B, Plan C gave a higher 1st-line RR (54% vs 29%) and PFS (median 8.7 vs 6.6 months) but shorter time to failure of the Plan (median 9.1 vs 11.6 months) (all p<0.001). Conclusions: Slightly increased survival was seen with combination chemotherapy, whether given 1st line or 2nd line, but this does not reach conventional levels of statistical significance. However, 1st-line combination chemotherapy did not improve OS compared with the same combinations deferred until 2nd line. Mature data will be presented at the meeting. No significant financial relationships to disclose.