FOLFIRI Cannot Be Administered Without 5-FU
FOLFIRI is a defined chemotherapy regimen that fundamentally requires 5-fluorouracil (5-FU) as one of its three essential components—removing 5-FU means you are no longer administering FOLFIRI. The regimen's name itself reflects its composition: FOLinic acid (leucovorin), Fluorouracil, and IRInotecan 1.
Understanding FOLFIRI's Standard Composition
The standard FOLFIRI regimen consists of 1:
- Irinotecan 180 mg/m² IV over 30-120 minutes on day 1
- Leucovorin 200 mg/m² IV infusion on days 1 and 2
- 5-FU 400 mg/m² IV bolus followed by 600 mg/m² IV continuous infusion over 22 hours on days 1 and 2
- Administered every 2 weeks
All three cytotoxic agents work synergistically, with leucovorin enhancing 5-FU's cytotoxicity 1.
Why 5-FU Cannot Be Omitted
Fluoropyrimidines Are the Backbone
Fluoropyrimidines (5-FU or capecitabine) form the backbone of all first-line palliative chemotherapy for metastatic colorectal cancer, whether used alone or in combination with other agents 1. The efficacy of 5-FU has been clearly demonstrated in elderly colorectal cancer patients, with infusional regimens proving more effective than bolus regimens 1.
Evidence for Complete Regimen
Multiple guidelines emphasize that FOLFIRI's efficacy depends on the complete combination 1:
- FOLFOX and FOLFIRI provide higher response rates, longer progression-free survival, and better overall survival than 5-FU/leucovorin alone 1
- Exposure to all three cytotoxics (fluoropyrimidines, oxaliplatin, and irinotecan) in various sequences results in the longest survival 1
- Elderly patients benefit from 5-FU/leucovorin/irinotecan therapy to the same extent as younger patients 1
What About Modifying the 5-FU Component?
Bolus 5-FU Can Be Omitted
Recent evidence shows that the 5-FU bolus portion can be safely omitted from FOLFIRI while maintaining the continuous infusion component 2. A large multicenter cohort study of 11,765 patients found that omitting the 5-FU bolus was not associated with decreased overall survival (HR 0.99; 95% CI 0.91-1.07; P=0.74) but resulted in 2:
- Reduced neutropenia (10.7% vs 22.7%; P<0.01)
- Reduced thrombocytopenia (11.2% vs 16.1%; P<0.01)
- Decreased use of granulocyte colony-stimulating factors (19.6% vs 29.1%; P<0.01)
However, this modification still includes 5-FU—it only removes the bolus while maintaining the continuous infusion 2, 3.
Infusional 5-FU Is Preferred
Guidelines consistently state that infusional 5-FU regimens are preferred over bolus regimens and are more effective 1. The NCCN explicitly notes that "infusional 5-FU is preferred. Bolus regimens of 5-FU are inappropriate as combination regimens with oxaliplatin or irinotecan" 1.
Alternative Regimens Without 5-FU
If 5-FU cannot be administered due to toxicity or contraindications, you would need to consider entirely different regimens, not "FOLFIRI without 5-FU":
Single-Agent Irinotecan
Irinotecan can be given as monotherapy, but this is a different treatment approach with different efficacy 1. Irinotecan-based therapy has been shown to be independently associated with improved survival in metastatic colorectal cancer 1.
Important Caveat
Using single-agent capecitabine as salvage therapy after failure on a fluoropyrimidine-containing regimen has been shown to be ineffective and is not recommended 1. This underscores that simply removing components from established regimens is not evidence-based practice.
Clinical Implications
When 5-FU Is Contraindicated
If a patient cannot receive 5-FU due to 1:
- Severe toxicity (mucositis, diarrhea, hand-foot syndrome)
- Dihydropyrimidine dehydrogenase (DPD) deficiency
- Other contraindications
You must select an alternative chemotherapy regimen entirely, not attempt to administer "FOLFIRI without 5-FU" 1. Options might include single-agent irinotecan or oxaliplatin-based regimens without fluoropyrimidines, though these are less established 1.
Sequential vs. Combination Therapy
For frail or selected patients, sequential therapy starting with fluoropyrimidine monotherapy remains a valid option 1. However, when an objective response is the primary goal (such as for surgical resection of metastases), combination chemotherapy remains the preferred option 1.
Common Pitfall to Avoid
Do not confuse modifying the 5-FU administration schedule (omitting bolus while keeping infusion) with completely omitting 5-FU from the regimen 2, 3. The former is supported by evidence; the latter fundamentally changes the regimen and is not FOLFIRI.