Toxic death-case after capecitabine + oxaliplatin (XELOX) administration: probable implication of dihydropyrimidine deshydrogenase deficiency.
This report here is the case of a 52-year-old male patient who suffered from extremely severe haematological toxicities (G4 neutropenia, G4 thrombocytopenia) while undergoing Xelox (Xeloda + Oxaliplatin) treatment for his multifocal hepatocarcinoma. Despite appropriate supportive treatment, his condition quickly deteriorated and led to death. It was hypothesized that dihydropyrimidine deshydrogenase (DPD) gene polymorphism could be, at least in part, responsible for this fatal outcome. To test this hypothesis, both phenotypic and genotypic studies were undertaken, and fully confirmed the DPD-deficient status of this patient. Uracil to dihydrouracil ratio in plasma was evaluated as a surrogate marker for DPD deficiency, and showed values out of the range previously recorded from a reference, non-toxic population. Interestingly, the canonical IVS14+1G>A single nucleotide polymorphism, usually associated with the most severe toxicities reported with 5-fluorouracil (5-FU), was not found in this patient, but further investigations showed instead a heterozygosity for the 1896C>T mutation located in the exon 14 of the DPYD gene. Taken together, the data strongly suggest for the first time that a toxic-death case after capecitabine-containing protocol could be, at least in part, linked with a DPD-deficiency syndrome. The case reported here warrants therefore systematic detection of patients at risk, including when oral capecitabine is scheduled.
Ciccolini
Joseph
J
Clinical Pharmacokinetics Department, La Timone University Hospital, Marseille, France.
Mercier
Cedric
C
Dahan
Laetitia
L
Evrard
Alexandre
A
Boyer
Jean-Christophe
JC
Richard
Karine
K
Dales
Jean-Philippe
JP
Durand
Alain
A
Milano
Gerard
G
Seitz
Jean-François
JF
Lacarelle
Bruno
B
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D001483:Base Sequence; D000069287:Capecitabine; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000188:drug therapy*; D017931:DNA Primers; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism*; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D020641:Polymorphism, Single Nucleotide; D014057:Tomography, X-Ray Computed
D017931:DNA Primers; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil