Fluorouracil Therapy and Genotype

Fluorouracil, or 5-flourouracil (5-FU), is a chemotherapy agent that belongs to the drug class of fluoropyrimidines. When given as an intravenous (IV) solution, 5-FU is used in the palliative management of carcinoma of many solid tumors including (but not limited to) colon, rectum, breast, esophagus, cholangiocarcinoma (bile duct cancers), stomach, and pancreas. When prescribed as a cream or solution for topical use, fluorouracil (brand names Carac, Efudex, Fluoroplex, Tolak) is used to treat multiple actinic or solar keratoses of the face and scalp. Capecitabine (brand name Xeloda or CAPE) is the oral pill form of 5-FU chemotherapy, which is used interchangeably with 5-FU IV chemotherapy. Although it is the same drug, the oral pill version has certain side effects that are more pronounced (for example, diarrhea or skin related side effects – ‘hand-foot’ syndrome). Given the common usage of 5-FU for a variety of malignancies and potentially fatal overdoses, an antidote has been developed—uridine triacetate—which may be useful for pharmacogenetic-related overdoses, as well. The gene encodes dihydropyrimidine dehydrogenase (DPD), an enzyme that catalyzes the rate-limiting step in fluorouracil metabolism. Genetic variations in the gene can lead to enzymes with reduced or absent activity. Individuals who have at least one copy of a non-functional variant [for example, (c.1905+1G>A) or (c.1679T>G)] will not be able to metabolize fluorouracil at normal rates. Consequently, they are at risk of potentially life-threatening fluorouracil toxicity, such as bone marrow suppression, diarrhea, and neurotoxicity. The prevalence of DPD partial deficiency varies in different populations but is approximately 35%. Complete absence of DPD function, which is often fatal with exposure to 5-FU chemotherapy, occurs in <1% (~0.2%) of the general population. The FDA-approved drug label for fluorouracil states that no dose of fluorouracil has been proven safe in individuals with absent DPD activity (Table 1). Fluorouracil is contraindicated in individuals who are known to have complete DPD deficiency, or when complete deficiency is suspected because of early-onset or unusually severe fluorouracil toxicity (1). The Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have published dosing recommendations for fluoropyrimidines (fluorouracil and capecitabine) based on genotype (Tables 2 and 3). Both recommendations include dose reductions for intermediate metabolizers (with reduced enzyme activity) and avoiding fluorouracil or capecitabine and choosing an alternative agent for poor metabolizers (with absent enzyme activity).