Evaluation of chemotherapy toxicities in patients receiving treatment for gastrointestinal cancers and therapeutic monitoring of 5-fluorouracil as a clinical support tool

Abstract

Background

5-Fluorouracil (5-FU) is essential in treating gastrointestinal cancers, but some patients show severe toxicity. The toxicity is exposure-related, which is linked to the enzyme dihydropyrimidine dehydrogenase (DPD) decoded by the DPYD gene. This study aimed to evaluate the possible toxicity related to 5-FU plasma levels, DPYD genotyping, and DPD phenotyping.

Methods

Forty-seven gastrointestinal cancer patients receiving 5-FU were included in this study. 5-FU plasma levels and DPD phenotyping were analyzed by UPLC-MS/MS. DPYD genotyping was also assessed. The Common Terminology Criteria for Adverse Events (CTCAE) was used to classify the toxicity.

Results

For hematological toxicity, 27.65% showed neutropenia, 78.72% anemia, and 29.78% thrombocytopenia. The area under the curve (AUC) of 5-FU calculated from the plasma was evaluated for three treatment cycles, and we observed that at the initial cycle, 48.93% were underexposed and 10.63% were overexposed, with a total of 59.56% of patients outside the therapeutic range. In the DPYD genotyping, 97.87% of patients had a wild-type genotype, and 2.12% had c.1236G>A mutation (E412E, rs56038477). A total of 82.97% of patients showed a phenotype compatible with normal DPD activity.

Conclusion

These findings suggest that the evaluation of DPYD genotyping and DPD phenotyping in the Brazilian population still requires further study. Moreover, the analysis of the plasma AUC of 5-FU could contribute to clinical routine, being a very useful tool, especially for identifying patients outside the therapeutic range and thus guiding more individualized doses, or even in the intervention of possible toxicities related to overexposure.