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PLoS One. 2015 Aug 26;10(8):e0135907. doi: 10.1371/journal.pone.0135907. eCollection 2015.

FFCD-1004 Clinical Trial: Impact of Cytidine Deaminase Activity on Clinical Outcome in Gemcitabine-Monotherapy Treated Patients.

Author information

1
SMARTc, CRO2 INSERM UMR S_911, Marseille, France.
2
University Hospital of Clermont Ferrand, Clermont Ferrand, France.
3
Center Jean Mermoz, Lyon, France.
4
University Hospital of Besançon, Besançon, France.
5
University Hospital of Toulouse, Toulouse, France.
6
Center Antoine Lacassagne, Nice, France.
7
University Hospital of Saint-Antoine and Pierre et Marie Curie, Assistance Publique des Hôpitaux de Paris, Paris, France.
8
University Hospital of La Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, France.
9
Fédération Francophone de Cancérologie Digestive FFCD, Dijon, France.
10
University Hospital of Caen, Caen, France.
11
University Hospital of Reims, Reims, France.
12
University Hospital of Nice, Nice, France.
13
University Hospital of Tours, Tours, France.
14
University Hospital of Angers, Angers, France.
15
Regional Hospital of Orleans, Orleans, France.
16
St Joseph Hospital, Paris, France.
17
Hospital of Toulon, Toulon, France.
18
University Hospital of Dijon, Dijon, France.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

CONCLUSION:

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01416662.

PMID:
26308942
PMCID:
PMC4550302
DOI:
10.1371/journal.pone.0135907
[Indexed for MEDLINE]
Free PMC Article

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