What is the effectiveness of single agent irinotecan (irinotecan) compared to FOLFIRI (Folinic acid, Fluorouracil, Irinotecan)?

FOLFIRI is Superior to Single-Agent Irinotecan

FOLFIRI (fluorouracil, leucovorin, and irinotecan) demonstrates superior effectiveness compared to single-agent irinotecan, though the context of use matters significantly. The evidence shows clear benefits in first-line settings but more nuanced findings in second-line therapy.

First-Line Therapy: FOLFIRI Shows Clear Advantage

In first-line treatment of advanced gastric and colorectal cancers, FOLFIRI consistently outperforms single-agent irinotecan across multiple efficacy measures:

• FOLFIRI achieved significantly higher objective response rates (39% vs 18%, p<0.0001) compared to single-agent irinotecan in first-line metastatic colorectal cancer 1
• The combination regimen demonstrated superior time to tumor progression and overall survival benefits in randomized phase III trials 1
• In gastric cancer, FOLFIRI is recognized by NCCN as an acceptable first-line option with favorable tolerability, while single-agent irinotecan lacks high-level evidence (category 1) for survival prolongation and is relegated to second- or third-line settings 2

Second-Line Therapy: Context-Dependent Effectiveness

The picture becomes more complex in second-line settings, particularly for colorectal cancer:

• A 2022 randomized trial in metastatic colorectal cancer patients who failed first-line XELOX/FOLFOX showed no significant difference in progression-free survival (3.5 vs 3.7 months, HR=1.084, p=0.6094), overall survival, or objective response rate between FOLFIRI and single-agent irinotecan 3
• Critically, single-agent irinotecan demonstrated a significantly more favorable toxicity profile with lower rates of grade 3-4 neutropenia (21.7% vs 47.7%), leucopenia, thrombocytopenia, mucositis, vomiting, and fever 3
• A 2011 meta-analysis of 29 trials confirmed that while combination treatment reduces alopecia and diarrhea compared to single-agent irinotecan, efficacy on clinical outcomes was similar in second-line settings 4

Toxicity Considerations

The toxicity trade-off is substantial and must be weighed against efficacy gains:

• In first-line colorectal cancer, FOLFIRI increases incidence of diarrhea, neutropenia, serious cardiovascular disorders, and severe thrombosis, though it extends median survival by approximately 3 months (to 15-17 months) 5
• For gastric cancer patients in poor clinical condition, FOLFIRI showed acceptable tolerability with only 16% grade 3-4 neutropenia and minimal grade 3 non-hematological toxicity, achieving a 40% response rate 6
• The irinotecan combination with fluorouracil and folinic acid (IF) demonstrated a more favorable toxicity profile than platinum-based regimens in gastric cancer, making it an alternative for patients unable to tolerate platinum therapy 2

Clinical Algorithm for Selection

For first-line therapy in advanced gastric or colorectal cancer:

• Choose FOLFIRI over single-agent irinotecan for patients with adequate performance status who can tolerate combination therapy 2, 1
• FOLFIRI is particularly appropriate when platinum-based regimens are contraindicated 2

For second-line therapy in metastatic colorectal cancer after oxaliplatin-based first-line:

• Single-agent irinotecan is a reasonable alternative to FOLFIRI, offering equivalent efficacy with reduced toxicity 3, 4
• Reserve FOLFIRI for patients with good performance status where the toxicity burden is acceptable 3

For gastric cancer specifically:

• FOLFIRI is acceptable for first-line therapy with demonstrated tolerability even in poor clinical condition 2, 6
• Single-agent irinotecan should be reserved for second- or third-line settings given lack of category 1 evidence for survival benefit 2

Common Pitfalls to Avoid

• Do not automatically assume combination therapy is always superior—the 2022 trial definitively showed equivalent outcomes with single-agent irinotecan in second-line colorectal cancer 3
• Avoid using single-agent irinotecan as first-line therapy for gastric cancer—guidelines clearly indicate it lacks sufficient evidence for this indication 2
• Do not overlook the substantial toxicity differences—neutropenia rates more than double with FOLFIRI in second-line settings (47.7% vs 21.7%) 3
• Consider that dose intensity matters: median relative dose intensity for irinotecan in combination regimens ranges from 72-87%, which may impact real-world effectiveness 1