FOLFOX in Advanced CRC

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de Gramont A, et al. "Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer". Journal of Clinical Oncology. 2000. 18(16):2938-2947.
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Clinical Question

Among patients with advanced colorectal cancer, does therapy with FOLFOX4 prolong progression free survival when compared to LV5FU2?

Bottom Line

Major Points

The backbone of colorectal cancer chemotherapy treatment for over 40 years has been the antimetabolite 5-fluorouracil (5FU). Trials in the early 1990s demonstrated that modulation with the folic acid derivative leucovorin (LV, combined LV5FU2) improves tumor response but not mortality.[1] The platinum-based cytotoxic agent oxaliplatin works synergistically with LV5FU2 and early trials were promising though a phase III of the combined regimen (called FOLFOX4) was lacking.

This publication published in 2000 by de Gramont et al. randomized 420 untreated patients with untreated colorectal cancer to either FOLFOX4 or LV5FU2. The FOLFOX4 group had longer PFS (9.0 vs. 6.2 months) and improved response rate (50.7% vs. 22.3%) though only a non-significant trend towards improved survival (16.2 vs. 14.7 months). FOLFOX4 was associated with higher rates of toxicities including neutropenia, diarrhea, and neuropathy though this did not adversely affect quality of life.



  • N=420
    • LV5FU2 (n=210)
    • FOLFOX4 (n=210)
  • Setting:
  • Enrollment:
  • Mean follow-up:
  • Analysis:
  • Primary outcome: Progression-free survival


Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

From the LV5FU2 group.

  • Demographics: Male 58.1%, age 63 years
  • WHO performance status:
    • 0: 48.6%
    • 1: 41.9%
    • 2: 9.5%
  • Primary site: Colon 70%, rectum 29%, multiple or not specified 1%
  • Metastases: Synchronous 66.2%, metachronous 33.3%, unknown 0.5%
    • Sites of metastasis: Liver 82.4%, lung 30.0%, other 11.4%
    • Number of sites: One 40%, ≥2 60%
  • Baseline labs:
    • CEA: Normal 17.6%, 1-20x normal 43.8%, >20x normal 34.8%, unknown 3.8%
    • Alk phos: Normal 53.3%, increased 45.2%, unknown 1.4%
    • LDH: 41.9%, increased 44.8%, unknown 13.3%
  • Adjuvant chemotherapy: Yes 20.5%, no 79.5%


  • Randomization to a group:
    • LV5FU2
    • FOLFOX4


Presented as LV5FU2 vs. FOLFOX4.

Primary Outcome

Progression-free survival
6.2 vs. 9.0 months (P=0.0003)

Secondary Outcomes

Response rate
22.3% vs. 50.7% (P=0.0001)
Overall survival
14.7 vs. 16.2 months (P=0.12)

Subgroup Analysis

Adverse Events

Neutropenia, NCI grade 3/4
5.3% vs. 41.7%
Diarrhea, NCI grade 3/4
5.3% vs. 11.9%
QoL impairment
No difference
Survival without progression of disease or deterioration in global health status
Longer with FOLFOX4 (P=0.004)



Further Reading

  1. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J. Clin. Oncol. 1992. 10:896-903.