Background
Phase III, open-label RCT. 2407 patients with curatively resected stage II (16%) or stage III (84%) colon cancer. Compared the addition of oxaliplatin to weekly 5-FU/leucovorin (FULV) — forming the FLOX regimen — in the adjuvant setting. Parallel to the European MOSAIC trial, which used FOLFOX4 vs infusional LV5FU2.
Interventions and follow up
Arm A: FLOX: oxaliplatin 85 mg/m² IV D1 + 5-FU 500 mg/m² IV bolus + leucovorin 500 mg/m² IV in weeks 1, 3, 5 of 8-wk cycles ×3 cycles (24 wks total)
Arm B: Weekly FULV: 5-FU 500 mg/m² IV bolus + leucovorin 500 mg/m² IV weekly ×6 of 8-wk cycles ×3 cycles
Primary endpoint: Disease-free survival (DFS)
Median follow-up: 8 yr (updated analysis)
Arm B: Weekly FULV: 5-FU 500 mg/m² IV bolus + leucovorin 500 mg/m² IV weekly ×6 of 8-wk cycles ×3 cycles
Primary endpoint: Disease-free survival (DFS)
Median follow-up: 8 yr (updated analysis)
Results
DFS: 8-yr DFS 63.9% vs 59.2%; HR 0.82, P=.002
OS: 8-yr OS 73.8% vs 70.1%; HR 0.88, P=.08 — not significant
OS: 8-yr OS 73.8% vs 70.1%; HR 0.88, P=.08 — not significant
Adverse events
GI: Grade ≥3 diarrhea 38% (FLOX) vs 25% (FULV) — most common added toxicity; nausea/vomiting grade ≥3 4.1% vs 2.4%
Neurologic/hematologic: Peripheral neuropathy grade ≥3 8.5% vs 0.7%; febrile neutropenia 4.0% vs 2.3%; treatment discontinuation 14% vs 9%
Neurologic/hematologic: Peripheral neuropathy grade ≥3 8.5% vs 0.7%; febrile neutropenia 4.0% vs 2.3%; treatment discontinuation 14% vs 9%
Conclusions
FLOX significantly improved DFS versus weekly FULV in adjuvant colon cancer, confirming the benefit of oxaliplatin addition first demonstrated in MOSAIC. The OS benefit trended but did not reach significance at 8 years, and the DFS benefit came with substantially higher rates of grade ≥3 diarrhea and peripheral neuropathy.
Key Limitations
The comparator is weekly bolus FULV, not infusional LV5FU2 (as in MOSAIC), making cross-trial comparisons imprecise. FLOX's weekly schedule differs from FOLFOX (biweekly) and was associated with unexpectedly high GI toxicity during early trial conduct, including rare treatment-related deaths from diarrhea/dehydration before protocol modification. OS benefit did not reach significance. FLOX is no longer a commonly used regimen — FOLFOX or CAPOX are preferred in practice.
Clinical Context
NSABP C-07 contributed supporting evidence for oxaliplatin-based adjuvant therapy in colon cancer. However, FOLFOX4 (MOSAIC) and CAPOX became the standard adjuvant regimens, not FLOX, due to the inferior tolerability profile of the weekly bolus schedule. Both MOSAIC and NSABP C-07 together led to FDA approval of oxaliplatin-based adjuvant regimens for stage III colon cancer in 2004.