ABSTRACT
5-Fluorouracil [5-FU] is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. Twenty-three patients were tested for DPD deficiency after excessive toxicities from 5-FU and/or capecitabine. DPD activity was evaluated by Peripheral Blood Mononuclear Cell [PBMC] radioassay, genotyping of DPYD gene by Denaturing High Performance Liquid Chromatography [DHPLC], or 2-13C uracil breath test [UraBT]. Of 23 patients with excessive toxicities from 5-FU and/or capecitabine, 7 [30%] were DPD deficient with a median age of 66 years, M:F ratio = 1.3:1 and ethnicities included Caucasian [71%], African-American [14%] and South-Asian [14%]. DPD activity ranged from 0.064 - 0.18nmol/min/mg. Three patients were treated with bolus 5-FU/LV, two with capecitabine, and two with high dose bolus 5-FU with 2', 3', 5'-tri-O-acetyluridine. Toxicities included mucositis [71%], diarrhea [43%], skin rash [43%], memory loss/altered mental status [43%], cytopenias [43%], nausea [29%], hypotension [14%], respiratory distress [14%] and acute renal failure [14%] Re-challenge with capecitabine in one patient after the Mayo regimen caused grade 3 hand-foot syndrome. Genotypic analysis of the DPYD gene in one patient with severe leucopenia demonstrated a heterozygous mutation [IVS14+1 G>A, DPYD]. The UraBT in two patients revealed 1 to be DPD-deficient [DOB50 of 112.8; PDR of 49.4%] and borderline normal values [DOB50 of 130.9; PDR of 52.5%] in a second patient. There were 2 toxicity-related deaths among DPD-deficient patients [28%]. DPD deficiency was observed in several ethnicities. Akin to 5-FU, capecitabine can also lead to severe toxicities in DPD-deficient patients. Screening patients for DPD deficiency prior to administration of 5-FU or capecitabine using UraBT could potentially lower risk of toxicity. Future studies should validate this technique