Fluorouracil (5-FU) is a remarkable drug that has been available for
41 years and has become the mainstay of chemotherapy for
gastrointestinal cancer.[1-7] It is one of a minority of drugs in
clinical medicine for which the qualitative spectrum of toxicity
changes dramatically when the drug is used in different doses and
schedules (Table 1). These
different methods of administration have been demonstrated to produce
significantly different toxicity patterns, particularly when bolus
schedules are compared to infusional schedules. For example, bolus
single-agent 5-FU given weeklywhich was, in the past, the
standard schedule and route of administration for this drug in
gastrointestinal canceris associated with myelosuppression as
its major toxicity, with mucositis and diarrhea being minor
toxicities. The major toxic event caused by 5-FU administered by
96-hour high-dose infusion is mucositis. Low-dose (250 to 300
mg/m²/d) continuous infusion of 5-FU is associated with little
myelosuppression but results in an unusual toxicity: palmar-plantar
dysesthesia, more commonly known as hand-foot syndrome. Finally, the
commonly used 5-FU/calcium folinate regimens, depending on the doses
and schedules, may produce the combination of mucositis, diarrhea,
and myelosuppression or, in weekly high-dose regimens, diarrhea as
the only significant toxicity.
Toxicity of 5-fluorouracil may also vary with the characteristics of
the patient. For example, in a large adjuvant colon cancer study, it
has been demonstrated that older patients (> 70 years) are more
likely to experience mucositis and myelosuppression from 5-FU/calcium
folinate regimens (Table 2).
It is also possible that the relatively rare neurotoxicity is more
common in older patients receiving 5-FU. Gender is another risk
factor for 5-FU toxicity. Female patients have a statistically higher
incidence of all 5-FU toxicities(Table
3). The latter finding may be associated with some degree of
decreased 5-FU catabolism in women. Fluorouracil toxicity may be
exacerbated by drugs that inhibit the major enzyme responsible for
5-FU metabolismdihydropyrimidine dehydrogenasesuch as the
irreversible inactivator 776C85 and the nucleic acid uracil.
Uracil acts as a competitive inhibitor of dihydropyrimidine
dehydrogenase and does not irreversibly inactivate the enzyme.
Strategies to treat or prevent 5-FUrelated toxicities include
general supportive measures and specific strategies, such as
prevention of mucositis by the use of oral ice chips, and treatment
of severe 5-FUrelated diarrhea with the somatostatin analog
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