Unpredicted Severe Toxicity after 5-Fluorouracil Treatment due to Dihydropyrimidine Dehydrogenase Deficiency
A 37-year-old female patient underwent curative resection for a stage II (pT3N0M0) poorly differentiated gastric adenocarcinoma, and this was followed by adjuvant chemotherapy consisting of 5-FU (600 mg/m2, i.v. on days 1 and 8) and epirubicin (50 mg/m2, i.v. on day 1) in 3-week cycles. However, the patient developed erythematous rashes on her hands and oral mucositis on day 5. Thus, day 8 of 5-FU administration was skipped. On day 14, the patient experienced fever, stomatitis, diarrhea, leucopenia (0.290×109/l), neutropenia (0.012×109/l), and thrombocytopenia (34×109/l). After supportive care with a granulocyte-colony stimulating factor (G-CSF) and broad-spectrum antibiotics, her fever decreased and her general condition and blood counts recovered after 1 week. On day 35, the patient then resumed her treatment with oral doxifluridine (200 mg t.i.d., a prodrug of 5-FU), but 3 days later she developed oral mucositis, and thus further medication was cancelled. Two weeks after this initial oral doxifluridine treatment, the patient presented at the emergency room due to severe oral pain and diarrhea (over 500 mL per day). A physical examination revealed grade 3 oral mucositis and erythematous rashes on her hands and feet. Her CBC revealed leucopenia (1.600×109/l), neutropenia (0.421×109/l), and thrombocytopenia (41×109/l), and after admission, the patient also manifested a fever of unidentified etiology. After 2 weeks of supportive care, the patient's CBC and systemic symptoms improved. Real-time quantitative polymerase chain reaction (PCR) then demonstrated that her DPD mRNA level was 2.5 (control group levels 30-80, cut-off value 3.0. Twenty-nine days after initial oral doxifluridine administration, the patient was discharged, and at the last follow-up 1 year after this after, she was doing well without any evidence of disease recurrence or sequelae of 5-FU toxicity.