Chemotherapy Drugs That Cause Diarrhea
The chemotherapy agents most commonly associated with diarrhea are fluorouracil (5-FU), capecitabine, and irinotecan, with combination regimens like capecitabine/irinotecan (CapeIRI) causing severe grade 3-4 diarrhea in up to 47% of patients. 1
High-Risk Chemotherapy Agents
Fluoropyrimidines
5-Fluorouracil (5-FU):
- Causes diarrhea in up to 50% of patients when combined with leucovorin (LV), with historical mortality rates reaching 5% in some studies 1
- The diarrhea may be watery or bloody and can lead to life-threatening sepsis when gut barrier disruption coincides with granulocyte nadir 1
- Risk is highest with bolus administration compared to continuous infusion, particularly with high-dose LV (500 mg/m²) 1
- Bolus 5-FU with folinic acid causes grade 3-4 diarrhea in 16% of patients 1
Capecitabine:
- An oral prodrug of 5-FU that causes diarrhea in 30-40% of patients at standard doses (2000 mg/m² per day for 14 of every 21 days), with 10-20% experiencing severe diarrhea 1
- Patients with dihydropyrimidine dehydrogenase (DPD) deficiency face life-threatening complications including severe diarrhea, mucositis, and pancytopenia 1
Topoisomerase Inhibitors
Irinotecan:
- Causes two distinct patterns of diarrhea 1:
- Acute (early-onset): Occurs immediately during or after infusion due to cholinergic properties, accompanied by abdominal cramping, rhinitis, lacrimation, and salivation; responds rapidly to atropine 0.25-1 mg subcutaneously or intravenously 1, 2
- Delayed (late-onset): Begins 6-14 days after administration, unpredictable and potentially life-threatening, more common with 3-weekly high-dose schedules than weekly dosing 1, 2
- Prophylactic atropine 0.5 mg subcutaneously may prevent acute diarrhea 2
Taxanes
Docetaxel:
- When combined with capecitabine, causes grade 3-4 diarrhea in 14% of patients 1
Cabazitaxel:
- Mentioned as causing diarrhea, though specific incidence data was truncated in the evidence 1
Highest-Risk Combination Regimens
The ESMO guidelines provide clear data on severe diarrhea rates with combination chemotherapy 1:
| Regimen | Grade 3-4 Diarrhea Rate |
|---|---|
| CapeIRI (capecitabine/irinotecan) | 47% |
| FOLFOXIRI (5-FU/LV/oxaliplatin/irinotecan) | 20% |
| mIFL (irinotecan/bolus 5-FU) | 19% |
| Bolus 5-FU with folinic acid | 16% |
| Irinotecan with 5-FU and folinic acid | 15% |
| Docetaxel with capecitabine | 14% |
| FOLFIRI (5-FU/LV/irinotecan) | 14% |
| FLOX (bolus 5-FU/LV/oxaliplatin) | 10% |
Critical Risk Factors to Assess
When evaluating diarrhea risk in patients receiving these agents, identify the following high-risk features 1:
- 5-FU co-administration with leucovorin (significantly increases risk)
- Unresected primary tumor
- Previous episodes of chemotherapy-induced diarrhea
- Female gender
- DPD deficiency (can cause life-threatening complications)
- History of gastrointestinal issues or previous abdominal radiation (as noted in the expanded question context)
Clinical Significance
Diarrhea from these agents can be dose-limiting and life-threatening 1. The disruption of gut integrity permits bacterial translocation and overwhelming sepsis, particularly when neutropenia coincides with severe diarrhea 1. In clinical trials of irinotecan and bolus 5-FU, diarrhea-associated mortality has been reported as high as 3.5% 3. Early recognition and aggressive management are essential to prevent morbidity and mortality 4, 5.
Additional Considerations
Beyond traditional cytotoxic agents, targeted therapies—particularly tyrosine kinase inhibitors—carry significantly elevated diarrhea risk (up to eightfold higher than conventional regimens), with up to 60% of patients experiencing diarrhea and 10% having severe diarrhea 6, 5. However, the question specifically addresses traditional chemotherapy agents like 5-FU, capecitabine, and irinotecan, which remain the primary culprits in chemotherapy-induced diarrhea requiring clinical vigilance.