Oral 5-FU Analogues in the Treatment of Breast Cancer

ABSTRACT: Three oral 5-fluorouracil (5-FU) therapies have been approved by the US Food and Drug Administration or are in development for the treatment of patients with breast cancer: capecitabine, UFT, and 5-FU/eniluracil. Capecitabine has been approved for breast cancer patients whose disease is paclitaxel-resistant, and either anthracycline-resistant or for whom further anthracycline use in not indicated. A response rate of 20% was observed in an open-label phase II trial of capecitabine in heavily pretreated patients with metastatic breast cancer. Diarrhea and hand-foot syndrome were the most frequently reported toxicities. In a randomized phase II study of capecitabine vs paclitaxel in breast cancer patients who had failed anthracyclines, response rates were 36% for capecitabine vs 21% for paclitaxel. Several phase II trials of 5-FU/eniluracil in breast cancer are ongoing. Preliminary response data from one of these trials on 31 patients with anthracycline- and taxane-resistant advanced breast cancer showed a 16% partial response rate. Grade 3-4 treatment-related toxicities included diarrhea (8%), nausea (3%), and granulocytopenia (3%). In Japan, UFT is widely used for the treatment of breast cancer in both the adjuvant and metastatic settings, though studies in the United States are just getting under way. A phase II trial conducted in Madrid, Spain evaluated the combination of UFT, methotrexate, and leucovorin as salvage therapy for breast cancer patients. The overall response rate was 38% among 21 patients, and diarrhea was the most common toxicity. Many questions remain unanswered about the optimal use of oral 5-FU agents in breast cancer. There seems little question that these agents have substantial activity and will find a place in the therapeutic armamentarium. [ONCOLOGY 12(Suppl 7):39-43, 1998]

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, 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, 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, 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 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]

5-FU/Eniluracil

Eniluracil is a potent inactivator of DPD, the first enzyme in the degradative pathway that rapidly reduces more than 80% of systemically administered 5-FU.[23] By combining eniluracil with 5-FU, the bioavailability of 5-FU is increased to virtually 100%, and the pharmacokinetic variability of oral 5-FU is decreased. With maximal inactivation of DPD (which occurs at eniluracil doses of 10 mg once daily), eniluracil increases the half-life of 5-FU by 20-fold, decreases 5-FU clearance by 20-fold, and causes no change in the volume of distribution of 5-FU as compared with 5-FU alone. Both drugs display linear pharmacokinetics in the dose ranges used in clinical studies. Therefore, 5-FU and eniluracil can be given with repeated dosing resulting in predictable exposure levels for patients and no unexpected accumulation. The effect is the simulation of continuous infusion 5-FU.

Two dosing regimens of the 5-FU/eniluracil combination have been evaluated in clinical trials—a 5-day regimen and a 28-day regimen. To date, phase II trials in women with breast cancer have been conducted only using the 28-day regimen. 5-FU and eniluracil are given in a combination pill twice daily for 28 days, repeated every 5 weeks. Although the maximum tolerated dose (MTD) of the 5-FU component was determined to be 1.8 mg/m², the standard phase II dosing is 5-FU 1.0 mg/m²/d and eniluracil 10 mg/m²/d given twice daily for 28 days. This dose was intended to achieve systemic exposure to 5-FU in the range at which clinical responses are seen with continuous-infusion 5-FU, without necessitating treatment interruptions or delays in subsequent courses. The dose-limiting toxicity for the 28-day regimen in all phase II trials has been diarrhea, with 8% of patients (who had a variety of tumors including colorectal cancer), experiencing grade 3/4 diarrhea. Hematologic toxicity has been uncommon, as with continuous-infusion 5-FU. Grade 3/4 neutropenia and thrombocytopenia occurred in 4% and 1% of patients, respectively. In contrast to continuous-infusion 5-FU, which has mucositis and hand-foot syndrome as dose-limiting toxicities, oral 5-FU/eniluracil was not associated with any grade 3/4 mucositis or hand-foot syndrome in patients participating in the phase II studies. Other nonhematologic toxicities included malaise, fatigue, and nausea and vomiting, but these were generally tolerable and manageable. Despite concerns raised in animal models, there has been no evidence to date of ophthalmic toxicity different from that observed with continuous-infusion 5-FU.

Four phase II trials are currently being conducted in patients with metastatic breast cancer. Preliminary results from one of these trials are available. Rivera et al evaluated the 28-day oral regimen of 5-FU/eniluracil in women with taxane- and anthracycline-resistant advanced breast cancer. Patients received oral 5-FU 1.0 mg/m²/d and eniluracil 10.0 mg/m²/d twice daily for the first 28 days of each 5-week course. Preliminary response data available for 31 patients demonstrate 5 partial responses (16%) and 5 patients with stable disease. Median duration of response has not yet been reached. Toxicity data are available on 40 patients to date. Grade 3/4 treatment-related toxicities included diarrhea (8%), nausea (3%), and granulocytopenia (3%) (Table 2). Hand-foot syndrome has not been reported.[24]

Two notes of caution regarding 5-FU/eniluracil deserve mention. First, renal elimination of unchanged 5-FU increases from less than 5% when 5-FU is given alone to 30% to 80% with the 5-FU/eniluracil combination. Because of this, patients with significant renal impairment should be treated with caution. A study is currently assessing whether dose must be adjusted for renal function. Second, because bleeding in association with prolonged prothrombin times has occurred in at least three patients receiving 5-FU/eniluracil and concomitant warfarin, it is recommended that patients taking these agents be monitored closely. Whether a drug interaction occurs has not been clearly determined.

UFT

Although initial studies of infusional tegafur were conducted in the United States in the 1970s and 1980s, the neurotoxic effects and lack of advantage of this compound over intravenous 5-FU led to the drug’s loss of appeal. In Japan, however, the oral formulation of tegafur, with its excellent bioavailability, continued to be developed and was eventually combined with uracil. This combination resulted in enhanced concentrations of 5-FU in tumors and improved antitumor effect. Pharmacokinetic studies showed that, though UFT and tegafur produced comparable levels of 5-FU in normal tissues and plasma, UFT produced 5- to 10-fold greater concentrations of 5-FU in tumor tissues.[19] UFT has since been studied with a daily dosing schedule in a variety of tumors and remains widely used in Japan for both the adjuvant and palliative treatment of breast cancer.

Phase I studies involving more than 170 patients confirmed that the MTD in long-term daily dosing trials was 600 mg/day in two or three divided doses. Similar to continuous-infusion 5-FU, the dose-limiting toxicities in the multiple dose trials were gastrointestinal, including nausea, vomiting, anorexia, and diarrhea. The daily dose of UFT recommended for phase II studies was generally 400-600 mg/day in two or three divided doses.[25,26]

Phase I studies conducted at M. D. Anderson and Memorial Sloan-Kettering Cancer Center (MSKCC), in which UFT was given in daily divided doses for 28 days followed by a 1- or 2-week rest period, respectively, also found diarrhea and abdominal discomfort to be dose-limiting. Recommended doses for phase II studies from these two trials were 360 mg/m²/day and 400 mg/m²/day, respectively.[27,28] Pharmacologic studies showed that peak plasma levels of tegafur were predictable, dose-related, and well-sustained over 6 hours following drug administration.[27-29]

Pooled data from a Japanese phase II study conducted at 211 institutions and involving nearly 700 patients given UFT 300-600 mg/day showed that anorexia, nausea/vomiting, diarrhea, and stomatitis were the most common adverse events. Hematologic toxicities were uncommon and generally mild. The response rate in the subset of patients with breast cancer was more than 30%.[26]

Phase I studies of UFT plus leucovorin were performed at M. D. Anderson Cancer Center. Patients received leucovorin 150 mg/day with escalating doses of UFT given daily for 28 days every 35 days. Diarrhea and asthenia were the primary adverse events. Although 350 mg/m²/day of UFT was considered the MTD, two of six patients treated at this dose experienced grade 3 diarrhea.[30]

A phase I study of the same design, performed at Roswell Park Cancer Center yielded similar results in terms of side effects, toxicities, MTD, and recommended dose for phase II studies.[31] Similar phase I trials performed at MSKCC and the University of Southern California, which used lower-dose leucovorin (15 mg/day), found the same MTD for UFT of 350 mg/m²/day for 28 days administered in 35-day cycles.

Phase II studies conducted at M. D. Anderson and Roswell Park Cancer Center used a 28-day-on and 7-day-off schedule of UFT 350 mg/m2/day and leucovorin at a fixed dose of 150 mg/d. Because of diarrhea experienced at the UFT 350 mg/m²/day dose at M. D. Anderson Cancer Center, the dose was reduced—only at that institution—to 300 mg/m²/day. Other phase II studies using low-dose leucovorin (15 mg/day) and UFT 350 mg/m²/day were conducted at MSKCC and the University of Southern California. None was exclusive to breast cancer, and data regarding response rates in breast cancer patients are not available. In all of these studies, asthenia and gastrointestinal toxicities, primarily diarrhea and stomatitis, were the principal toxicities. To date, no phase II studies using UFT, with or without leucovorin, for the treatment of breast cancer have been reported in the United States.

At some centers outside of the United States, UFT is being substituted for bolus 5-FU in combination regimens. Investigators at the Philippines General Hospital conducted a comparative trial of oral UFT and infusional 5-FU in combination with cyclophosphamide and doxorubicin for the treatment of patients with metastatic breast cancer. Thirty-one patients were treated with UFT 350 mg/m²/day × 14 days, cyclophosphamide 500 mg/m² IV day 1, and doxorubicin 50 mg/m² IV day 1. Another 31 patients had the UFT replaced in the regimen by 5-FU 500 mg/m² IV on days 1 and 8. The regimens were repeated every 28 days for six cycles. No differences in response rates or times-to-progression were seen, but the small number of patients in the trial precludes any definitive conclusions. Both regimens were well tolerated and produced similar toxicity profiles; however, anemia and stomatitis were significantly more common in the 5-FU arm.[32]

Investigators in Madrid have also published preliminary results of a phase II trial of UFT, methotrexate, and leucovorin as salvage therapy for breast cancer patients who had progressive disease after high-dose chemotherapy with autologous stem cell support. The methotrexate (100 mg/m²) was given by intramuscular injection on day 1. UFT 300 mg/m²/day and leucovorin 60 mg/day were administered on days 2-20, each in four daily divided doses. Cycles were repeated every 21 days. The overall response rate was 38% among 21 treated patients. Diarrhea was the most common toxicity (29% of patients with grades 2/3), and other toxicities were mild.[33]

Future Directions

The three oral 5-FU drugs —capecitabine, UFT, and 5-FU/eniluracil—show promise as effective, tolerable chemotherapeutic agents for possible future use as single-agent therapy in the palliative setting and as components of combination therapy in the palliative and adjuvant settings. Potential avenues of investigation include combinations of these agents with other chemotherapeutic drugs that have nonoverlapping side effects, as well as their potential use in all-oral regimens. Once the new oral platinum analogs and vinca alkaloids become available, such combination oral regimens may be achievable. Concomitant use of these drugs with radiation also seems attractive, given the radiosensitizing effects of 5-FU. Clearly, this remaking of an old class of agents represents a new trend in cancer treatment, one that offers hope for a more simple, effective, and tolerable means of delivering chemotherapy.

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