Prolonged Severe 5-Fluorouracil-Associated Neurotoxicity in a Patient with Dihydropyrimidine Dehydrogenase Deficiency

Abstract

5-Fluorouracil (5-FUJ is an analogue of pyrimidine nucteosides that is widely used in the treatment of head and neck, breast, ovarian, and colon cancer. Stomatitis, diarrhea, dermatitis, and myelosuppression are the main toxicities of 5-FU. A less frequent side effect that is becoming more recognized is neurologic toxicity. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of 5-FU. DPD deficiency follows an autosomal recessive pattern of inheritance, and its prevalence is estimated to be 3%. Cancer patients who are receiving 5-FU treatment and are DPD deficient can develop severe side effects. The neurologic toxicity can vary from being mild to severe and prolonged. We describe the side effects of 5-FU in a colon cancer patient who suffered severe mucositis, desquamating dermatitis, prolonged myelosuppression, and neurologic toxicity that required admission to the intensive care unit. The patient remained hospitalized for 3 months. Recovery from the side effects was complete 4 months after the last 5-FU treatment. Subsequent testing revealed that this patient has an extremely low level of DPD activity (0.015 nmol/min/mg protein; mean, 0.189 nmol/min/mg protein). Because neurologic toxicity is becoming more recognized and DPD affects the catabolism of 5-FU, we discuss management issues and the use of new DPD inhibitors. We also discuss whether screening for DPD deficiency is warranted to identify patients at risk for severe toxicities from 5-FU treatment.

Key Words:

• Neurotoxicity
• 5-Fluorouracil
• Colon cancer chemotherapy
• Dihydropyrimidine dehydrogenase deficiency