Colorectal Carcinoma Adjuvant and Chemotherapy
Chemotherapy for colorectal cancer (CRC) is typically
applied in the following two clinical settings: (1) for the
adjuvant management of curatively resected early-stage disease
and (2) for the primary management of unresectable
distant metastases. Until the early 1990s, options for
chemotherapy were essentially limited to 5-fluorouracil (5-
FU). Recent exciting advances have resulted in the integration
of new agents, including oxaliplatin and irinotecan,
for the treatment of patients with advanced disease with
consequent significant improvements in survival benefit.
Although 5-FU remains the mainstay of treatment for
adjuvant therapy, efforts to evaluate the role of oxaliplatin
and irinotecan in this setting are already underway.
Primary Chemotherapy for Advanced CRCs
Developed in 1957, 5-FU represents one of the earliest
examples of a rationally designed drug, and now, almost
five decades later, it still remains the base of almost all CRC
chemotherapy regimens. Following metabolic activation
to 5-fluoro-2´-deoxyuridylate (FdUMP), this fluorinated
pyrimidine combines with methylenetetrahydrofolate
(CH2FH4) to form a ternary complex with thymidylate
synthase (TS) thus interfering with DNA synthesis by
inhibiting the conversion of deoxyuridylate to thymidylate.
Additional mechanisms of action include direct incorporation
into ribonucleic acid (RNA) to interfere with
RNA transcription and, to a lesser extent, direct incorporation
into deoxyribonucleic acid (DNA).
ADVERSE EFFECTS
Hematologic effects and gastrointestinal (GI) mucosal toxicity
are the common dose-limiting toxicities of 5-FU. Severe
diarrhea (³ grade 3 as defined by the National Cancer
Institute Common Toxicity Criteria) will be experienced
by 30% of patients, and grade 3 stomatitis can be anticipated
in 15 to 20% of patients. The risk of nausea and vomiting
is low.
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