In this issue of Oncology, Dr. Schilsky has provided a comprehensive yet concise review of the pharmacology of the fluoropyrimidines and, in particular, capecitabine(Drug information on 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(Drug information on 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 nucleoside phosphorylase.
Pharmacokinetics of Capecitabine
Capecitabine (N-4-pentyloxycarbonyl-5´-deoxy-5-fluorocytidine) 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(Drug information on 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 with interest.
Third, recent studies demonstrating a survival advantage for irinotecan(Drug information on 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 continuous-infusion 5-FU.