Background
Phase III randomized trial in 420 patients with adenocarcinoma of the colon or rectum and unresectable metastatic disease, previously untreated for advanced disease. Tested whether adding oxaliplatin to infusional 5-FU/leucovorin (FOLFOX4) improves progression-free survival as first-line therapy.
Interventions and follow up
Arm A: FOLFOX4 (oxaliplatin 85 mg/m2 plus LV 200 mg/m2, 5-FU 400 mg/m2 bolus then 600 mg/m2 22-h infusion) every 2 weeks
Arm B: LV5FU2 (LV 200 mg/m2, 5-FU 400 mg/m2 bolus then 600 mg/m2 22-h infusion) every 2 weeks
Primary endpoint: Progression-free survival (PFS)
Median follow-up: 27.7 mo
Arm B: LV5FU2 (LV 200 mg/m2, 5-FU 400 mg/m2 bolus then 600 mg/m2 22-h infusion) every 2 weeks
Primary endpoint: Progression-free survival (PFS)
Median follow-up: 27.7 mo
Results
Median PFS: 9.0 mo vs 6.2 mo, FOLFOX4 vs LV5FU2 (P=.0001)
Response rate: 50.7% vs 22.3% (P=.0001)
Median OS: 16.2 mo vs 14.7 mo (P=.12) — not significant
Response rate: 50.7% vs 22.3% (P=.0001)
Median OS: 16.2 mo vs 14.7 mo (P=.12) — not significant
Adverse events
Hematologic: Grade ≥3 neutropenia 41.7% vs 5.3%, FOLFOX4 vs LV5FU2
Neurologic: Grade 3 neuropathy 18.2% vs none; overall any-grade neurosensory toxicity 68% vs 18%
GI: Grade ≥3 diarrhea 11.9% vs 5.3%, mucositis 5.8% vs 1.5%
Neurologic: Grade 3 neuropathy 18.2% vs none; overall any-grade neurosensory toxicity 68% vs 18%
GI: Grade ≥3 diarrhea 11.9% vs 5.3%, mucositis 5.8% vs 1.5%
Conclusions
Adding oxaliplatin to infusional 5-FU/leucovorin (FOLFOX4) significantly improved PFS and response rate over LV5FU2 in metastatic colorectal cancer, though the overall survival difference was not statistically significant, establishing FOLFOX as a first-line option.
Key Limitations
The primary PFS benefit did not translate into a significant OS gain, partly attributable to crossover and post-progression therapy. Oxaliplatin-related cumulative sensory neuropathy is a notable toxicity. Predates biomarker-driven therapy.
Clinical Context
This trial established the FOLFOX4 regimen and helped lead to FDA approval of oxaliplatin in colorectal cancer. FOLFOX remains an ESMO-endorsed first-line chemotherapy doublet for mCRC, typically combined with a biologic agent selected by RAS status and primary tumor sidedness.