Pharmacology and Clinical Status of Capecitabine

In treating cancer, discovering new ways to use or modify old drugs can sometimes be as valuable as the identification of new drugs. This point is elegantly illustrated in Dr. Schilsky’s article about capecitabine (Xeloda), a prodrug that leads to high intratumoral levels of fluorouracil (5-FU).

Continuous vs Bolus Infusion of Chemotherapy

The schedule of drug administration is probably as important as dose, although the dose question has been studied more systematically in randomized, controlled trials. In five of six randomized trials comparing continuous vs bolus infusion of 5-FU in patients with metastatic colon cancer, the continuous-infusion regimen produced a higher response rate or an improvement in survival.[1] In most of these studies, the differences in effect were not statistically significant. However, in a meta-analysis of these studies, the response rate was significantly higher for patients randomized to continuous-infusion 5-FU (22% vs 14%, odds ratio = 0.55, P = .0002), as was the survival rate (hazard ratio = 0.88, P = .04).[1] There was also less toxicity associated with the continuous-infusion treatment.

The greater efficacy of continuous-infusion therapy may be related to the possibility that the mechanism of action for 5-FU is different depending on the mode of administration (see “Strategies to Optimize 5-FU Therapy,” in Dr. Schilsky’s article). The difference in toxicity profile may be due to the fact that the schedule of administration for 5-FU affects drug distribution.[2] For example, we know that continuous infusion results in lower drug levels in the bone marrow. Changes in drug distribution may also explain why palmar-plantar erythrodysesthesia (hand-foot syndrome) is experienced with the continuous infusion of not only 5-FU, but a number of other cytotoxic agents, including doxorubicin.

There are insufficient data from studies involving other tumor types and the continuous infusion of other drugs to draw general inferences about the relative benefits of continuous vs bolus infusion. However, numerous studies have demonstrated that patients with end-stage breast cancer previously treated with bolus 5-FU will respond to continuous-infusion 5-FU, and that this is the most effective, least toxic treatment available for these patients.[3]

In addition, a recently reported randomized trial included continuous 5-FU as one component of a combination. Results showed an insignificant trend towards a higher response rate (34% vs 31%), a 3-year relapse-free survival rate (77% vs 66%), and a significant improvement in 3-year overall survival (90% vs 80%, P = .04) for the arm that included infusional 5-FU.[4] Since this study was confounded by differences in the cytotoxic regimens used in the two arms, it does not provide proof of principle. However, observations of the high response rate associated with continuous-infusion 5-FU among patients with end-stage disease, combined with the results in previously untreated patients, suggest that this approach deserves further study in breast cancer.

Continuous Infusion and Drug Dose

One reason that continuous-infusion treatment has not generated more interest in the oncology community is that lower doses must be used when a drug is administered continuously. This should probably be of less concern to us now that multiple randomized trials comparing different doses of chemotherapy have failed to demonstrate evidence of a steep dose-response curve for most cytotoxic agents used to treat the most common solid tumors.[5,6]

However, it is also possible that one of the reasons for our failure to leverage the dose concept in clinical oncology may be that while substantially increasing the dose of drug administered to the patient we have failed to substantially increase the dose of drug that reaches the tumor. This could change if we were able to selectively target tumor tissue, thus avoiding toxicity to normal tissues while continuously administering drug.

Greater Efficacy, Decreased Toxicity

Capecitabine and other modifiers of 5-FU pharmacokinetics described by Dr. Schilsky may provide an opportunity to simultaneously achieve continuous exposure and high doses—ie, a high intratumoral area under the curve (AUC). These drugs are given orally and thus can be administered daily. In addition, they appear to selectively target tumor tissue, thereby providing a much higher intracellular concentration of 5-FU than can be achieved with a similar dose of 5-FU. Theoretically, at least, these fluoropyrimidines and inhibitors of dihydropyrimidine dehydrogenase should be more effective than 5-FU if dose and schedule are important variables.

Since these new drugs offer selective targeting of tumor tissue, they might be just as effective as 5-FU, but at a much lower and much less toxic dose. It has long been a standard operating principle to use all cytotoxics at their maximum tolerated dose—a principle first demonstrated in the pivotal trials used for registering capecitabine. Although capecitabine is relatively nontoxic, it is associated with a high incidence of palmar-plantar erythrodysesthesia.

It seems likely that the palliative benefits of capecitabine therapy might be achieved with almost no toxic cost if lower doses were used. In a retrospective analysis of four phase II trials of capecitabine for metastatic breast cancer, 131 patients were found to have had a dose reduction, while 190 patients were treated at full doses.[7] No significant differences were observed in the response rate, duration of response, time to treatment failure, or survival between the two groups.

References:

1. Efficacy of intravenous, continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer: Meta-analysis Group in Cancer. J Clin Oncol 16:301-308, 1998.

2. Fraile RJ, Baker LH, Buroker TR, et al: Pharmacokinetics of 5-fluorouracil administered orally by rapid intravenous and by slow infusion. Cancer Res 40:2223-2228, 1980.

3. Smith IE: Continuous infusional chemotherapy for early breast cancer: The Royal Marsden Hospital Experience. Recent Results Cancer Res 152:323-327, 1998.

4. Smith IE, A’Hern RP, Howell A, et al: Preoperative continuous-infusional ECISF (epirubicin, cisplatin, and infusional 5-FU) vs conventional AC chemotherapy for early breast cancer: A phase III multicentre, randomized trial by the TOPIC trial group (abstract). Proc Am Soc Clin Oncol 19:84a, 2000.

5. MacNeil M, Eisenhauer EA: High dose chemotherapy: Is it standard management for any common solid tumor? Ann Oncol 10:1145-1161, 1999.

6. Coleman RE: High dose chemotherapy, rationale and results in breast carcinoma. Cancer 88:3059-3064, 2000.

7. O’Shaughnessy J, Blum J: A retrospective evaluation of the impact of dose reduction in patients treated with Xeloda (capecitabine) (abstract). Proc Am Soc Clin Oncol 19:104a, 2000.