title: FFCD-1004 Clinical Trial: Impact of Cytidine Deaminase Activity on Clinical Outcome in Gemcitabine-Monotherapy Treated Patients.
abstract: OBJECTIVE
  Because cytidine deaminase (CDA) is the key enzyme in gemcitabine metabolism, numerous studies have attempted to investigate impact of CDA status (i.e. genotype or phenotype) on clinical outcome. To date, data are still controversial because none of these studies has fully investigated genotype-phenotype CDA status, pharmacokinetics and clinical outcome relationships in gemcitabine-treated patients. Besides, most patients were treated with gemcitabine associated with other drugs, thus adding a confounding factor. We performed a multicenter prospective clinical trial in gemcitabine-treated patients which aimed at investigating the link between CDA deficiency on the occurrence of severe toxicities and on pharmacokinetics, and studying CDA genotype-phenotype relationships.
  
  
  METHODS
  One hundred twenty patients with resected pancreatic adenocarcinoma eligible for adjuvant gemcitabine monotherapy were enrolled in this study promoted and managed by the Fédération Francophone de Cancérologie Digestive. Toxicities were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4. They were considered severe for grade ≥ 3, and early when occurring during the first eight weeks of treatment. CDA status was evaluated using a double approach: genotyping for 79A>C and functional testing. Therapeutic drug monitoring of gemcitabine and its metabolite were performed on the first course of gemcitabine.
  
  
  RESULTS
  Five patients out of 120 (i.e., 4.6%) were found to be CDA deficient (i.e., CDA activity <1.3 U/mg), and only one among them experienced early severe hematological toxicity. There was no statistically significant difference in CDA activity between patients experiencing hematological severe toxicities (28.44%) and patients who tolerated the treatment (71.56%). CDA genetic analysis failed in evidencing an impact in terms of toxicities or in CDA activity. Regarding pharmacokinetics, a wide inter-individual variability has been observed in patients.
  
  
  CONCLUSIONS
  This study, which included only 4.6% of CDA-deficient patients, failed in identifying CDA status as a predictive marker of toxicities with gemcitabine. A lack of statistical power because of smoothing effect of CDA variability as compared with real life conditions could explain this absence of impact.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01416662.
authors: SMARTc, CRO2 INSERM UMR S_911, Marseille, France.
authors: Cindy
authors: C
authors: Serdjebi
authors: University Hospital of Clermont Ferrand, Clermont Ferrand, France.
authors: Johan
authors: J
authors: Gagnière
authors: Center Jean Mermoz, Lyon, France.
authors: Jérôme
authors: J
authors: Desramé
authors: University Hospital of Besançon, Besançon, France.
authors: Francine
authors: F
authors: Fein
authors: University Hospital of Toulouse, Toulouse, France.
authors: Rosine
authors: R
authors: Guimbaud
authors: Center Antoine Lacassagne, Nice, France.
authors: Eric
authors: E
authors: François
authors: University Hospital of Saint-Antoine and Pierre et Marie Curie, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors: Thierry
authors: T
authors: André
authors: University Hospital of La Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, France.
authors: Jean-François
authors: JF
authors: Seitz
authors: Fédération Francophone de Cancérologie Digestive FFCD, Dijon, France.
authors: Carole
authors: C
authors: Montérymard
authors: University Hospital of Caen, Caen, France.
authors: Dominique
authors: D
authors: Arsene
authors: University Hospital of Reims, Reims, France.
authors: Julien
authors: J
authors: Volet
authors: University Hospital of Nice, Nice, France.
authors: Abakar
authors: A
authors: Abakar-Mahamat
authors: University Hospital of Tours, Tours, France.
authors: Thierry
authors: T
authors: Lecomte
authors: University Hospital of Angers, Angers, France.
authors: Véronique
authors: V
authors: Guerin-Meyer
authors: Regional Hospital of Orleans, Orleans, France.
authors: Jean-Louis
authors: JL
authors: Legoux
authors: St Joseph Hospital, Paris, France.
authors: Gaël
authors: G
authors: Deplanque
authors: Hospital of Toulon, Toulon, France.
authors: Pierre
authors: P
authors: Guillet
authors: SMARTc, CRO2 INSERM UMR S_911, Marseille, France.
authors: Joseph
authors: J
authors: Ciccolini
authors: University Hospital of Dijon, Dijon, France.
authors: Côme
authors: C
authors: Lepage
authors: University Hospital of La Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, France.
authors: Laetitia
authors: L
authors: Dahan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000378:metabolism*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D054316:Biomarkers, Pharmacological; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine