Oral 5-FU Analogues in the Treatment of Breast Cancer

Introduction

The pyrimidine analogue 5-fluorouracil (5-FU) has evoked interest for more than 30 years because of its broad antitumor activity, as well as its synergism with leucovorin, other antineoplastic agents, radiation, and physiologic nucleosides. The observation that rat hepatomas more avidly utilized radiolabeled uracil than normal cells prompted the hypothesis that the metabolic pathways for the utilization of uracil and its analogues differed in malignant cells.[1] Such a difference could, and eventually would, be exploited with the use of the fluorinated pyrimidines, among them 5-FU. 5-FU is converted intracellularly to 5-fluoro-2'-deoxyuridylate (FdUMP) and fluorouridine triphosphate (FUTP). FdUMP binds thymidylate synthase, thereby preventing the formation of thymidylate and inhibiting DNA synthesis. FUTP is incorporated into RNA as a fraudulent base producing various functional inhibitions and suppression of tumor cell multiplication.

For decades, 5-FU has been used in combination with other antineoplastic agents in the adjuvant treatment of breast cancer and either in combination therapy or as a single agent in the palliative treatment of advanced breast cancer. Because of the drug’s short half-life (6 to 20 minutes) and the dependence of its activity upon duration of exposure, a variety of different schedules have been investigated. Early trials used the traditional bolus delivery exemplified in the standard CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), 5-FU) regimens.[2-6] Others sought to overcome the short half-life of 5-FU either by giving the drug more frequently, by modulating its activity with leucovorin, or both. Several groups have investigated treating women with metastatic breast cancer with 5 consecutive days of intravenous leucovorin 500 mg/m²/d followed 1 hour later by IV bolus 5-FU 340-400 mg/m²/d. Cycles were repeated every 28 days. Overall response rates ranged from 24% to 44%, and responses were seen in patients previously treated with 5-FU. The primary dose-limiting toxicities of this regimen were mucositis, diarrhea, and conjunctivitis, with only moderate hematologic toxicity observed.[7-10] Other investigators used a weekly regimen of 5-FU and leucovorin, which had previously demonstrated efficacy in the treatment of colorectal cancer.

Alternatively, attempts at circumventing the short half-life of 5-FU have included delivering the drug by prolonged continuous infusion. Several phase II studies have assessed the efficacy of continuous-infusion 5-FU in patients with previously treated metastatic disease.[11-16] Response rates have ranged from 12% to 54%; an overall response rate of 29% was reported in a review of 199 patients.[17] Many of these patients had been heavily pretreated, had poor performance status, and had previously received 5-FU.

 Chu et al examined the use of continuous-infusion 5-FU as first-line therapy in a small trial of women with metastatic breast cancer.[18] Patients received continuous-infusion 5-FU 250 mg/m²/day for 5 weeks in 6-week cycles. The objective response rate was 44%. As in other studies of continuous intravenous administration, toxicities were manageable and were primarily mucosal and cutaneous; 13% of patients had grade 3 mucositis. Hematologic toxicity was minimal. One patient had an indwelling catheter infection requiring catheter removal.[18]

Oral 5-FU Agents

The new oral 5-FU agents are being developed to achieve the activity and tolerability of continuous-infusion 5-FU without the inconvenience, cost, or catheter complications associated with infusional treatment. One oral agent capecitabine(Drug information on capecitabine), has been approved by the Food and Drug Administration (FDA). Two others, UFT and 5-FU/eniluracil, are in development (Table 1).

Capecitabine is a fluoropyrimidine carbamate that is a prodrug of 5'-deoxy-5-fluorouridine (5-DFUR), which is converted to 5-FU. Unlike 5-FU, which has poor bioavailability, capecitabine is readily absorbed from the gastrointestinal tract. In the liver, a carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytadine (5'-DFCR). Cytidine deaminase, an enzyme present in most tissues, including tumors, converts 5'-DFCR to 5-DFUR. Another enzyme, thymidine phosphorylase, also present in most tissues and expressed in high amounts in many carcinomas, hydrolyzes 5'-DFUR to 5-FU.

UFT is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (also known as tegafur(Drug information on tegafur), ftorafur, or FT) and uracil in a 1:4 molar concentration. Tegafur is also a prodrug of 5-FU. Like capecitabine, tegafur is nearly completely absorbed after oral administration and undergoes gradual hepatic conversion to 5-FU. Coadministration with uracil inhibits the degradation of 5-FU to a-fluoro-B-alanine and may also act to preferentially increase the concentration of 5-FU in tumor cells vs plasma or normal tissues.[19]

Unlike capecitabine and UFT, which are prodrugs of 5-FU, 5-FU/eniluracil is a combination of 5-FU and an irreversible dihydropyrimidine dehydrogenase (DPD) inactivator. DPD is the first enzyme in the degradative pathway of pyrimidine bases. By inhibiting the degradation of 5-FU, eniluracil increases the half-life of 5-FU, simulating the effect of a continuous infusion.

Clinical Trials With Oral Fluoropyrimidine Agents

Capecitabine

Capecitabine (Xeloda) was the first of the three oral agents to gain approval from the FDA for the treatment of metastatic breast cancer. It is currently approved for patients whose disease is resistant to paclitaxel(Drug information on paclitaxel) and either resistant to anthracyclines or for whom further anthracycline use is not indicated (eg, cumulative doses of > 400 mg/m²).

Capecitabine was evaluated in an open-label, single-arm, phase II study conducted at 24 centers in North America.[20] A total of 162 patients with bidimensionally measurable (n = 135) or clinically evaluable (n = 27) metastatic breast cancer were treated with 2,510 mg/m²/day in two divided doses for 2 weeks followed by a 1-week rest period repeated in 3-week cycles. The patients had received at least two, but not more than three, previous chemotherapeutic regimens for metastatic disease. All had previously received and demonstrated resistance or failure to paclitaxel therapy. More than 90% of the patients had previously received anthracyclines and 82% had received 5-FU. The overall response rate in patients with measurable disease was 20%. All responding patients had received an anthracycline, 59% and 26% of whom were deemed resistant or to have failed, respectively. Three complete responses were seen (with durations of 106, 109, and 194+ days). The median duration of response was 8.1 months, with a median survival of 12.8 months. Median time-to-progression (TTP) was 93 days. Diarrhea and hand-foot syndrome were the only grade 3/4 toxicities noted, occurring in 14% and 10% of patients, respectively (Table 2). Myelosuppression was uncommon, and alopecia was not observed. Only 3.7% of patients had grade 4 treatment-related adverse events, and no treatment-related deaths occurred.[20]

Similar results were demonstrated in a randomized phase II study of capecitabine vs CMF as first-line therapy for metastatic breast cancer, in which the CMF group was used as a reference arm.[21] Patients were treated with the same 3-week capecitabine regimen as in the previous study. A total of 95 women were randomly assigned to received capecitabine (n = 62) or CMF (n = 33). Overall response rates were 25% (95% confidence interval [CI], 14% to 37%) for capecitabine and 16% (95% CI, 5% to 33%) for CMF. Median TTP was 132 days in the capecitabine group (95% CI, 91-213) and 94 days in the CMF group (95% CI, 74-147). Toxicities were reported more frequently than in the previous phase II study—44% of capecitabine patients and 20% of CMF patients had grade 3/4 nonhematologic toxicities. Toxicities that occurred most frequently in capecitabine patients were again hand-foot syndrome (16%) and diarrhea (8%). All toxicities were adequately controlled with either treatment interruption or dose reduction. Grade 3/4 hematologic toxicity was more frequent with CMF (47%) than capecitabine (20%).[21]

Capecitabine was compared with paclitaxel in a randomized phase II study of breast cancer patients who had failed previous anthracycline therapy in which paclitaxel was used as a control arm.[22] Standard doses of both agents were used (capecitabine 2,510 mg/m²/day in two divided doses given on days 1 to 14 every 21 days vs paclitaxel 175 mg/m² IV given on day 1 every 21 days). The study was interrupted prematurely because of difficulty identifying patients who were willing to be randomized. Forty-two patients received either capecitabine (n = 22) or paclitaxel (n = 20). The response rate in the capecitabine group was 36% (95% CI, 17% to 59%) including 3 complete responses vs 21% (95% CI, 6% to 46%) with no CRs in the paclitaxel group. Grade 3/4 nonhematologic events were reported by 22% of capecitabine patients and 58% of paclitaxel patients. Grade 3/4 hematologic toxicity occurred in 18% and 68% of patients, respectively.[22]