Key result
Low-dose capecitabine linked to severe toxicity driven by an MTHFR mutation despite normal DPD screening.
Why the study?
Some patients experience severe capecitabine toxicity despite normal DPD screening, and the role of MTHFR variants in this toxicity is not well documented, especially in the Chinese population.
Does insufficient MTHFR activity contribute to severe capecitabine toxicity in patients with normal DPD screening?
Case Report (n=1)
Does insufficient MTHFR activity contribute to severe capecitabine toxicity in patients with normal DPD screening?
Severe capecitabine toxicity may occur in patients with normal DPD screening due to insufficient MTHFR activity.
MTHFR variants may explain severe capecitabine toxicity despite normal DPD; leaves open whether testing should guide dosing.
Capecitabine is an oral prodrug metabolized into 5-fluorouracil (5-FU) and serves as a representative anticancer agent. While fluoropyrimidine treatment is usually well-tolerated, a subset of patients unfortunately experiences severe and sometimes life-threatening toxicity related to these compounds. This adverse reaction is frequently attributed to partial or complete deficiencies in the dihydropyrimidine dehydrogenase (DPD) enzyme. However, some patients may still suffer from severe toxic effects despite normal DPD screening results when treated with capecitabine. This paper presents the case of a Chinese woman with stage IIIB moderately differentiated adenocarcinoma of the lower rectum (cT3N2aM0) who exhibited severe toxicity after two weeks of neoadjuvant concurrent chemoradiotherapy in TNT mode at a low dose (825mg/m2 bid) of capecitabine. We found that this severe toxicity might be attributable to insufficient methylenetetrahydrofolate reductase (MTHFR) activity. To our knowledge, such reports are scarce in the medical literature concerning the Chinese population.
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Li et al. (2024) conducted a case report in Rectal cancer and severe capecitabine toxicity (n=1). Capecitabine was evaluated on Severe toxicity (grade IV myelosuppression, severe diarrhea). A Chinese woman with stage IIIB rectal cancer developed severe toxicity after receiving low-dose capecitabine, likely attributable to a heterozygous MTHFR (677C>T) mutation despite normal DPD screening.
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