Despite adequate primary treatment at the time of diagnosis (surgery
with or without adjuvant radiation or chemotherapy), 25% to 30% of
patients with no histologic signs of axillary node involvement and up
to 80% of node-positive patients relapse and die of metastatic breast
cancer.[1,2] Although adjuvant treatment may delay recurrence and
improve survival in a small number of patients, therapy for
metastatic disease remains palliative in intent. Some lengthening of
survival duration has been demonstrated with combination regimens in
selected patients with advanced disease.
Metastatic breast cancer is moderately sensitive to anticancer
chemotherapy. Mean objective response rates of 20% to 50% have been
achieved by treatment with single-agent anthracyclines, alkylating
agents, fluorouracil (5-FU), methotrexate, vinca alkaloids, and, more
recently, taxanes.[5-7] Regimens that combine anthracyclines and
taxanes are very effective and provide the highest overall response
rates (up to 90%) as front-line therapy for advanced disease.[8,9] In
the future, these combinations may be used in the adjuvant and/or
neoadjuvant settings. There remains, nonetheless, the need for
new, nonanthracycline, non-taxanebased, combination regimens
that are effective in patients with metastatic breast cancer.
Vinorelbine (Navelbine) is a semisynthetic derivative of vinblastine.
Both drugs exert their antineoplastic action by preventing tubulin
polymerization and arresting mitosis at metaphase. [11,12]
Vinorelbine was specifically designed to bind with mitotic
tubulin, and in early studies in breast cancer, it provided
activity similar to the anthracyclines. As a result of its
structural modification, vinorelbine has a reduced effect on axonal
microtubules compared with other vinca alkaloids, and consequently
may be less neurotoxic.
In phase II studies, single-agent, intravenous (IV) vinorelbine 30
mg/m² weekly as first-line chemotherapy for metastatic disease
produced response rates of 41% to 60% in patients with advanced
breast cancer.[15-20] In studies of second-line therapy, vinorelbine
yielded overall response rates of 17% to 36% in patients with
previously treated breast cancer. [19,21-23] Although most phase II
studies were designed to administer single-agent vinorelbine at a
dose of 30 mg/m²/wk,[12,18] the mean dose intensity achieved was
only 65% to 70% of the planned dose (20 to 23 mg/m²/wk) due to
dose delays for neutropenia and/or its complications.
In one double-blind, randomized study, 56 evaluable patients with
advanced breast cancer received either UFT (uracil and tegafur) at
400 mg/d or tegafur at 800 mg/d. Although there was no statistical
significance in response rate between the two arms (39% in the UFT
arm and 21% in the tegafur arm), there was a trend favoring UFT for
median time to progression: 37 weeks in the UFT arm vs 28 weeks in
the tegafur arm (P = .09).
In a phase II study of first-line treatment of metastatic breast
cancer, Daniels et al evaluated the combination of UFT 10 mg/kg/d and
leucovorin 90 mg/d (days 7 to 21) with carboplatin (Paraplatin) 100
mg/m²/d (days 1 to 3) and etoposide (VePesid) 100 mg/m²/d
(days 1 to 3). The response rate was 48% among 23 evaluable patients.
Grade 3 neutropenia occurred in five patients and diarrhea in
three. Recently, Villalon et al performed a randomized phase II
study of UFT at 350 mg/m²/d (days 1 to 14) vs 5-FU at 500
mg/m²/d (days 1 and 8), both in combination with doxorubicin
(Adriamycin) at 50 mg/m² and cyclophosphamide (Cytoxan, Neosar)
500 mg/m² on day 1. Among 62 evaluable patients, there was no
statistical difference in overall response rate (UFT: 48.4%; 5-FU:
35.5%); median response duration was 16 weeks in both arms. Toxicity
was low with both regimens.
Vinorelbine has been combined with 5-FU as a continuous infusion or
with 5-FU plus leucovorin. In first-line treatment of metastatic
breast cancer, vinorelbine (30 mg/m² on days 1 and 5) combined
with 5-FU (750 mg/m² in a continuous infusion from days 1 to 5)
produced a 61.6% response rate in 63 evaluable patients. Using
the same schedule, Vogel et al reported a 40% overall response rate
among 47 evaluable patients with metastatic breast cancer.
Second-line therapy of vinorelbine (30 mg/m² on day 1) plus 5-FU
(750 mg/m²/d in a continuous infusion on days 1 to 3) yielded an
overall response rate of 31% in 16 patients. In all of these
studies, however, toxicity was greater than that noted with
single-agent vinorelbine, and the 30- to 25-mg/m²/wk starting
doses were not maintained throughout treatment. In a phase II pilot
study by Mardiak et al, 15 previously untreated patients with
metastatic breast cancer receiving vinorelbine at 20 mg/m² (days
1 and 8) in combination with 5-FU at 500 mg/m² (days 1 and 8)
and leucovorin at 200 mg/m² (days 1 and 8) experienced a 73% (11
of 15 patients) overall response rate.
Thus, given the need for new, effective, nonanthracycline,
non-taxanebased chemotherapies for metastatic breast cancer,
and based on the significant single-agent clinical activities of
vinorelbine and UFT plus leucovorin, a nonrandomized, phase I, dose-escalating
study of their combination was planned. The primary objectives were
to determine the maximum tolerated dose, dose-limiting toxicity, and
recommended doses of UFT plus leucovorin and vinorelbine for the
treatment of metastatic breast cancer in patients who had previously
received one chemotherapy regimen. In addition, the pharmacokinetics
of UFT plus leucovorin and vinorelbine used in combination were evaluated.
Women aged ³ 18 years with metastatic
breast cancer were accrued into this phase I, dose-finding study,
conducted at three centers. The trial received ethical committee
approval and all patients provided written, informed consent.
Inclusion was based on histologically proven breast cancer with
evidence of measurable and/or evaluable metastatic disease. Patients
must have received one prior chemotherapy regimen for the treatment
of metastatic breast carcinoma. Prior neoadjuvant and/or adjuvant
chemotherapy was permitted. Cytotoxic or radiation therapy must have
been terminated for at least 4 weeks.
Other eligibility criteria were World Health Organization (WHO)
performance status £ 2, absolute
neutrophil count (ANC) ³ 2 ´ 109/L,
platelet count ³100 ´ 109/L,
serum creatinine £1.5 ´
upper limit of normal, aspartate transaminase and alanine
transaminase £ 2 ´
upper limit of normal, and bilirubin £
1.25 ´ upper limit of normal.
Patients previously treated with a vinca alkaloid or a continuous
infusion of 5-FU, either in the adjuvant or metastatic setting, were ineligible.
Starting doses for the combination of vinorelbine and UFT plus
leucovorin were lower than those recommended for the respective
single agents, but were still expected to yield acceptable levels of
efficacy, as described earlier. Thus, the first dosage level was
vinorelbine 15 mg/m² on days 1, 8, and 15, and UFT 300 mg/d plus
a fixed leucovorin dose of 90 mg/d, both in three divided daily doses
on days 1 through 21. Vinorelbine was injected on days 8 and 15,
provided ANC > 1.5 ´ 109/L
and platelets > 75 ´ 109/L.
Treatment cycles were repeated every 28 days, provided blood cell
counts had recovered and any nonhematologic toxicity had resolved to
grade £ 1. Treatment could be delayed
for up to 2 weeks if ANC remained < 1.5 ´ 109/L
and/or platelet count was < 75 ´ 109/L.
The prophylactic use of a recombinant human granulocyte colony-stimulating
factor was not routinely permitted.
Doses of vinorelbine and UFT were escalated in each successive cohort
of new patients (Table 1).
Three patients were treated at each dose level, with a 2-week
interval between the entry of the first patient and the next two
patients. Intraindividual dose escalation was not permitted. If one
of three patients at one dose level developed a dose-limiting
toxicity, three more patients were entered at the same dose level.
Patients who experienced dose-limiting toxicity were removed from
treatment until the toxicity had resolved to grade £
1, and then restarted for the subsequent cycle at the next lower dose
level. Doses that had been reduced for toxicity in individual
patients could not be reescalated.
Because of significant dose-limiting toxicities reported at dose
level 2, which was considered the maximum tolerated dose, the study
was amended and the dose-escalation scheme was modified (Table
2). For subsequent levels, the administration of vinorelbine on
day 15 was removed.
Dose-Limiting Toxicity and Maximum Tolerated Dose
Toxicity was graded according to the National Cancer Institutes
Common Toxicity Criteria. Dose-limiting toxicity was defined during
the first cycle as (1) any of the following hematologic toxicities:
grade 4 neutropenia lasting > 7 days, febrile neutropenia (defined
as grade 4 neutropenia plus fever grade ³
2), or grade 4 thrombocytopenia; (2) grade 3/4 nausea, vomiting, or
diarrhea despite appropriate treatment; (3) any other nonhematologic
toxicity grade 3/4 (with the exception of alopecia and fatigue); (4)
inability of patients to take full UFT doses during ³
3 of 21 days; (5) delay in start of the second cycle (day > 29);
and (6) inability to take one of the three vinorelbine doses for dose
levels 1 and 2 or one of the two vinorelbine doses for the subsequent
dose levels because of toxicity.
The maximum tolerated dose was defined as the dose at which two or
more of three, or three or more of six, patients developed a
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