title: 5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases.
abstract: OBJECTIVE
  5-Fluorouracil (5-FU) is a mainstay for treating various solid tumours in adults, including digestive and head and neck cancers. 5-FU-related toxicities usually include haematological, digestive and cutaneous features. Additionally, 5-FU has been described as being potentially neurotoxic in patients, but these side effects are quite rare in clinical practice. Here, we report two cases of sudden and unpredictable drug-induced neurotoxicities that occurred in patients undergoing their first course of 5-FU-based chemotherapy.
  
  
  METHODS
  None of these patients had any previous neurological disorder history, and both were treated following standard regimen (LV-5-FU2 and TPF for patient 1 and 2, respectively). Neurotoxicity included drowsiness, acute confusion plus dysarthria for the first patient and seizure, confusion and signs of metabolic encephalopathy for the second one. In addition, typical 5-FU-related severe toxicities (e.g. neutropenia and mucosities) were observed. Both patients slowly recovered from these neurological toxicities under supportive treatment. It was assumed that overexposure to 5-FU could explain the severe toxicities encountered. To test this hypothesis, we retrospectively evaluated the dihydropyrimidine dehydrogenase (DPD) activity of these patients on a phenotypic basis.
  
  
  RESULTS
  Evaluation of the uracil-to-di-hydrouracil (U/UH2) ratio in plasma revealed a profound DPD deficiency syndrome in both patients.
  
  
  CONCLUSIONS
  These cases suggest that 5-FU standard dosage administration may lead to strong overexposure, responsible for the severe toxicities observed, including the neurological features. It implies that DPD deficiency can cause neurotoxicity in 5-FU-treated patients and advocates for the prospective screening of DPD deficiency before starting any 5-FU-containing chemotherapy so as to prevent such side effects in the future.
authors.affiliation: Hôpital d'Instruction des Armées Laveran, Marseille, France. pierre-yves.cordier@laposte.net
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Cordier
authors.forename: André
authors.initials: A
authors.lastname: Nau
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.forename: Manuela
authors.initials: M
authors.lastname: Oliver
authors.forename: Cédric
authors.initials: C
authors.lastname: Mercier
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
authors.forename: Eric
authors.initials: E
authors.lastname: Peytel
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D001921:Brain / Q000473:pathology; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000150:complications*; D004569:Electroencephalography / Q000187:drug effects; D017034:Epilepsy, Frontal Lobe / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000150:complications / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D020258:Neurotoxicity Syndromes / Q000134:cerebrospinal fluid / Q000473:pathology*; D020127:Recovery of Function; D012811:Sigmoid Neoplasms / Q000150:complications / Q000188:drug therapy; D014057:Tomography, X-Ray Computed; D014498:Uracil / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C007419:dihydrouracil; D014498:Uracil; D005472:Fluorouracil