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

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Consort flowchart of the primary objective in the FFCD-1004 clinical trial.

Fig 2. Pharmacokinetics profiles of gemcitabine (A) and its metabolite (B) overtime during the first round of gemcitabine administration in pancreatic adenocarcinoma cancer patients.

Patients have been sampled before infusion, at the end, and 90 and 120 minutes after ending the infusion. A wide inter-individual variability is observed, either for gemcitabine or for dFdU.

Fig 3. Boxplots of CDA activity in prospective compared to retrospective study.

CDAretro stands for CDA activity in gemcitabine-treated patients for various types of cancers in the retrospective study. The boxplot in the middle represents CDA activity in the subgroup of gemcitabine-monotherapy patients in the retrospective study. CDA activities of patients from the prospective study are represented in the boxplot on the right. Isolating gemcitabine-monotherapy treated patients leads to a smoothing effect in CDA activity variability.