Management of FOLFIRI Plus Aflibercept in a Patient with Hyperbilirubinemia and Liver Metastases
Irinotecan should be used with caution and with decreased doses in patients with elevated serum bilirubin (47.40 μmol/L, normal <20). Dose reduction of irinotecan is required before proceeding with FOLFIRI plus aflibercept in this patient with liver metastases. 1
Assessment of Liver Function and Irinotecan Metabolism
- The patient's bilirubin level (47.40 μmol/L) is more than twice the upper limit of normal, indicating impaired liver function likely due to liver metastases
- Irinotecan metabolism is significantly affected by hyperbilirubinemia, as it is primarily metabolized through the UGT1A1 enzyme pathway 1, 2
- Patients with elevated bilirubin are at increased risk for irinotecan-related toxicities, including severe neutropenia and diarrhea
Recommended Approach
Dose Modification for Irinotecan
- Reduce the initial dose of irinotecan by at least 25-50% of the standard dose 1, 3
- Consider UGT1A1 genotyping to further guide dosing decisions, particularly if available 2
- Monitor closely for signs of irinotecan toxicity (neutropenia, diarrhea, fatigue)
Management of Aflibercept
- Aflibercept has only shown activity when given in conjunction with FOLFIRI in FOLFIRI-naïve patients 1
- Aflibercept can be administered at standard doses as its metabolism is not directly affected by hyperbilirubinemia
- Be aware that aflibercept may increase the chemotherapy-related adverse events including diarrhea, neutropenia, asthenia, and stomatitis 1
Monitoring During Treatment
- Perform weekly complete blood counts during the first cycle
- Monitor liver function tests before each treatment cycle
- Assess for signs of increased toxicity:
- Severe diarrhea (≥ grade 3)
- Neutropenia (ANC < 1500/mm³)
- Fatigue or asthenia
- Hypertension (aflibercept-related)
- Proteinuria (aflibercept-related)
Alternative Treatment Options to Consider
If toxicity is excessive or liver function deteriorates:
- Consider switching to an oxaliplatin-based regimen (FOLFOX) which may be better tolerated in patients with liver dysfunction 1
- For patients with impaired tolerance, consider infusional 5-FU/LV or capecitabine with or without bevacizumab as an alternative 3
- Bevacizumab may be preferred over aflibercept based on toxicity and/or cost considerations 1
Important Caveats
- Discontinuation rates due to adverse events are higher with aflibercept (26.6%) compared to placebo (12.1%) in clinical trials 1
- The VELOUR trial showed modest improvement in overall survival with FOLFIRI plus aflibercept (13.5 months) versus FOLFIRI plus placebo (12.1 months) 1
- There are no data to suggest activity of FOLFIRI-aflibercept in patients who have progressed on FOLFIRI-bevacizumab, or vice versa 1
- Close monitoring by a multidisciplinary team is essential to balance efficacy with toxicity management
By implementing these recommendations, you can safely administer FOLFIRI plus aflibercept to this patient with hyperbilirubinemia and liver metastases, while minimizing the risk of severe toxicity.