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Pharmacogenomics. 2019 Aug;20(13):931-938. doi: 10.2217/pgs-2019-0028.

Lethal toxicities after capecitabine intake in a previously 5-FU-treated patient: why dose matters with dihydropryimidine dehydrogenase deficiency.

Author information

1
Department of Hematology Oncology & Internal Médicine Centre Hospitalier d'Aix en Provence, Aix-en-Provence, France.
2
Medical Biology Department, APHM Marseille, France.
3
SMARTc Unit, Pharmacokinetics Laboratory, CRCM UMR Inserm 1068, Aix Marseille Univ Marseille, France.

Abstract

Dihydropryimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome associated with severe or lethal toxicities with oral capecitabine. Usually, patients with history of 5-FU-based therapy with no signs for life-threatening toxicities are considered as not DPD-deficient individuals who can be safely treated next with capecitabine if required. Here we describe the case of a woman originally treated with standard FEC100 protocol for metastatic breast cancer with little severe toxicities but grade-3 mucosities that were quickly resolved by symptomatic treatment. When switched to capecitabine + vinorelbine combo, extremely severe toxicities with fatal outcome were unexpectedly observed. Pharmacogenetic investigations were performed on cytidine deaminase and DPYD, and showed that this patient was heterozygous for the 2846A>T mutation on the DPYD gene. DPD phenotyping (i.e., uracil plasma levels >250 ng/ml, dihydrouracil/uracil ratio <0.5) confirmed that this patient was profoundly DPD deficient. Differences in fluoropyrimidine dosing between FEC100 (i.e., 500 mg/m2 5-FU) and capecitabine (i.e., 2250 mg daily) could explain why initial 5-FU-based protocol did not lead to life-threatening toxicities, whereas capecitabine rapidly triggered toxic death. Overall, this case report suggests that any toxicity, even when not life threatening, should be considered as a warning signal for possible underlying profound DPD deficiency syndrome, especially with low-dose protocols.

KEYWORDS:

5-FU, capecitabine; dihydro pyrimidine dehydrogenase; toxic death

PMID:
31486738
DOI:
10.2217/pgs-2019-0028

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