Dihydropyrimidine dehydrogenase (DPD) evaluation in 5-fluorouracil (5FU)-based therapies for gastrointestinal (GIC) and breast cancer (BC) patients (pts)

Abstract

13535 Background: DPD plays a key role in the metabolism of 5FU and pts with deficiency of DPD suffer from severe toxicity. We developed a specific LC-MS/MS method to measure the DPD enzymatic activity in PBMC from pts treated with 5FU, as prescreening method. We measured the rate of 5FU degradation in PBMC. Materials and Methods: 10 μg/l of 5FU was added to PBMC and incubated at 37°C up to 2.0h. Concentration of 5FU was measured by a LC-MS/MS system and results were expressed as pg/min/106 cells of degraded 5FU. Blood samples were obtained from consecutive pts with GIC and BC treated with 5FU-based schedules. Toxicities were assessed according to NCI CTC 3. Results: 59 pts included, median age of 69y (40–84), M/F 37/22 (62.7/37.3%); neoplasms were colorectal/pancreatic-biliary/gastric/oesophageal/breast 44/9/4/1/1 (74.6/15.2/6.8/1.7/1.7%). 5FU based therapies: chemotherapy (CT) alone as adjuvant in 22/59 pts (37.3%), I line and ≥ II line in 22 and 4 pts (37.3 and 6.8%), 59.3% were polyCT; CTRT in 11/59 pts (18.6%). The DPD values were divided into 4 groups: values ≤0.68, ≥0.68 <1.12, ≥1.12 <1.36 identified a severe (SD), mild (MD), minimal (MIND) deficiency, respectively; values ≥1.36 identified a normal activity (N). None patient had SD of DPD. MD/MIND was shown in 5/8/43 pts (8.5/13.6/72.9%) with a median value of 0.9 (SD ± 0.11, 0.75–1.02)/1.27 (SD ± 0.05, 1.20–1.34)/4.40 (SD ± 2.36, 1.38–13.72), respectively. In the MD group, Haematological, Diarrhoea, Vomiting, Mucositis, Neurotoxicity G0–2/G3 toxicities were showed in 80/20, 60/40, 100/0, 80/20 and 20% of pts, respectively; in MIND group maximum toxicities were all G1 and, in the N group, G3–4 toxicities were Haematological/Diarrhoea/Vomiting/Mucositis/Neurotoxicity/Acute Renal Failure (ARF) in 11/9/4.7/4.7/7/2% of pts, respectively. ARF and G4 haematological toxicities were reported in 2 pts with high values of DPD (13.72 and 7.45). Conclusions: pts with normal-high DPD has been shown to be at risk of developing mild toxicity by 5FU; the analysis showed a trend toward greater toxicity in those pts with normal values of DPD than those with lower values. Higher toxicities rates have been shown in pts with very high levels of DPD. Recruitment is still ongoing. No significant financial relationships to disclose.