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Oral 5-FU Analogues in the Treatment of Breast Cancer

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]

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