Anticipating gemcitabine-related severe/lethal toxicities: A feasibility study

Abstract

14652 Background: Gemcitabine is an antimetabolite drug extensively used for treating solid tumors in adults. Gemcitabine pharmacokinetics is altered by Cytidine Deaminase (CDA) gene polymorphism, resulting in impaired detoxification, systemic overexposure and potentially severe toxicities in deficient patients. To ensure a better safety in the handling of gemcitabine, we have developed a simple and rapid phenotypic test to determine the CDA status in patients with cancer. The aim of this work was to evaluate the feasibility and relevance of screening CDA status in patients undergoing gemcitabine-based therapy. Methods: CDA status was evaluated by measuring spectrophotometrically the residual CDA activity in serum. This retrospective study was performed in 100 adult patients (56M/44F, 64± 16 years) with either lung, pancreatic or vesical cancers. Early toxicities were monitored following standard NCI grading. Results: Four patients (2M/2F, mean age 68± 9 years, mean gemcitabine dose: 1200± 240 mg/m2) displayed early severe toxicities (e.g., > grade 3), including one toxic-death. Mean recorded CDA activities in non-toxic patients were 3.5± 2 U/mg protein. Conversely, mean CDA activities in patients with severe/lethal toxicities upon gemcitabine intake were as low as 0.8± 0.14 U/mg (i.e., -77% vs non-toxic patients), thus suggesting that CDA deficiency could be at the origin of the side-effects reported. Conclusions: In this study, 4% of the patients administred with gemcitabine displayed severe or lethal (1%) toxicities. All of them showed marked impairment in CDA function, as measured with the phenotypic test we used. These preliminary data strongly suggests, therefore, that our simple test could be of interest in a routine setting to detect CDA-deficient patients at risk with gemcitabine, a major drug extensively used in clinical oncology. No significant financial relationships to disclose.