In this issue of Oncology, Dr. Schilsky has provided a
comprehensive yet concise review of the pharmacology of the
fluoropyrimidines and, in particular, capecitabine (Xeloda).
Pyrimidine nucleoside phosphorylase (thymidine phosphorylase)
catalyzes the formation of pyrimidine bases from nucleosides. Levels
of this enzyme have been shown to be significantly higher in tumor
tissue, as compared to normal tissue. Recently, pyrimidine nucleoside
phosphorylase has been shown to be a tumor-associated angiogenic
factor, identified as platelet-derived endothelial cell growth
factor, whose expression has been correlated with poor clinical outcome.
A substrate for this enzyme, deoxyfluorouridine, was synthesized in
an attempt to increase the efficacy of fluorouracil (5-FU) by
increasing intratumoral delivery of the drug. In subsequent
clinical testing, response rates similar to those reported at that
time for 5-FU in colorectal carcinoma (30% to 35%) could be obtained
only after protracted continuous venous infusionup to 90 days
in one study. Subsequent trials of oral administration were
limited by diarrhea, due presumably to the release of 5-FU in the
gastrointestinal tract through the activity of intestinal pyrimidine
Pharmacokinetics of Capecitabine
was developed to circumvent the problem of gastrointestinal toxicity
associated with oral deoxyfluorouridine. This oral prodrug of 5-FU is
absorbed through the gastrointestinal mucosa as an intact molecule.
It is sequentially activated by carboxylesterase, cytidine deaminase,
and pyrimidine nucleoside phosphorylase. This cascade of enzymatic
reactions results in the formation of 5´-deoxy-5-fluorocytidine, 5´-deoxy-5-fluorouridine,
and finally, the intratumoral release of 5-FU.
In human tumor xenograft models, capecitabine yields substantially
higher concentrations of 5-FU within tumors than in plasma or normal
tissue. In addition, capecitabine yields higher intratumoral
concentrations of 5-FU than equitoxic doses of 5-FU.
In phase I studies, two schedules of capecitabine and one schedule of
capecitabine in combination with leucovorin were tested. On a
twice-daily oral schedule for 6 weeks, the maximum tolerated dose was
1,331 mg/m²/d. On a twice-daily dose for 14 days with 1 week
off, the recommended phase II dose was 2,510 mg/m². This
latter dose offered the best toxicity profile, and therefore was
selected for subsequent studies.
Pharmacokinetic data revealed a rapid, near complete absorption of
capecitabine with rapid conversion to metabolites and low systemic
exposure to 5-FU. Diarrhea was dose limiting; other toxicities, such
as palmar-plantar erythrodysesthesia (hand-foot syndrome) and
stomatitis, were typical of toxicities seen with protracted-infusion
5-FU. In the routine clinical use of capecitabine for breast
cancer, the most common toxicity leading to discontinuation of
therapy is hand-foot syndrome.
As discussed in the Schilsky review, the antitumor activity of
capecitabine has been demonstrated in breast and colorectal cancers.
Studies in other fluorouracil-responsive tumors are ongoing.
Considerations in Capecitabine Therapy
Numerous issues remain regarding the role of capecitabine in the
management of solid tumors. First, data from completed randomized
studies in colorectal cancer fail to demonstrate any survival
advantage for capecitabine-treated patients over 5-FU/leucovorin
recipients.[9,10] Capecitabine achieved a better toxicity profile and
higher response rate than 5-FU/leucovorin. Pharmacologically,
however, it could be argued that a more valid comparison of efficacy
would be between capecitabine and continuous-infusion 5-FU.
Second, capecitabine has yet to be proven superior to other oral
fluoropyrimidines in clinical tests. Table
2 of the Schilsky article lists oral fluoropyrimidines in
clinical development. While capecitabine offers a theoretical
advantage because of the predominant intratumoral conversion to 5-FU,
it is unclear whether this will translate to a meaningful survival
benefit in the clinical setting when compared to other agents.
In this regard, comparative toxicities of these agents may be more
important, since clinical efficacy may be similar. S-1, an oral
formulation of tegafur and its modulators, may theoretically cause
less gastrointestinal toxicity because of the inhibition of
gastrointestinal pyrimidine phosphoribosyl transferase. This
enzyme activates 5-FU to fluorouridine monophosphate, and
consequently, fluorouridine triphosphate (5-FUTP), which is
incorporated into RNA. This incorporation of 5-FUTP into RNA is
thought to primarily mediate the gastrointestinal toxicity of
5-FU. Results of maturing studies with this agent are awaited
Third, recent studies demonstrating a survival advantage for
irinotecan (Camptosar) in combination with 5-FU/leucovorin over
5-FU/leucovorin raise important questions about the utility of
single-agent oral fluoropyrimidines in the treatment of colorectal cancers.
Finally, oncologists need to be more circumspect about claims that
capecitabine is a tumor-activated or
tumor-specific fluoropyrimidine. While thymidine
phosphorylase has been shown to be more abundant in numerous tumor
tissues as compared to normal tissue, this enzyme exists in
significant amounts in the gastrointestinal mucosa, liver, and other
normal tissues, which are therefore perfectly capable of converting
capecitabine to 5-FU. As evidence of this, the toxicities of
capecitabine are not inconsequential and mimic the toxicities of
continuous-infusion 5-FU. In the experience of this author, a
significant number of women with breast cancer are unable to tolerate
the suggested dose of 2,500 mg/m² given for 14 days.
Therefore, until more studies mature, capecitabine should probably be
considered a convenient, but only slightly more efficacious form of
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