Despite adequate primary treatment at the time
of diagnosis (surgery with or without adjuvant radiation or
chemotherapy), 25% to 30% of patients without histologic signs of
axillary node involvement, and up to 80% of node-positive patients
relapse and subsequently 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,
however, has been demonstrated with combination regimens in selected
patients with advanced disease.
Metastatic breast cancer is moderately sensitive to anticancer
chemotherapy, and mean objective response rates of 20% to 50% have
been achieved with single-agent treatment with anthracyclines,
alkylating agents, 5-fluoro-uracil (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 will potentially be
used in adjuvant and/or neoadjuvant situations. There remains,
nonetheless, the need for new, non-anthracycline,
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, it provided activity similar to that of the
anthracyclines. As a result of vinorelbines structural
modification, it has a reduced effect on axonal microtubules compared
with other vinca alkaloids, and as a result, may be less neurotoxic.
In phase II studies, single-agent intravenous 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 an overall response rate of 17% to 36% in patients with
previously treated breast cancer.[19,21-23] Although most phase II
studies have been designed to administer single-agent vinorelbine at
a dose of 30 mg/m² weekly,[12,18] the mean dose intensity
achieved has only been 65% to 70% of the planned dose (20-23
mg/m²/week) due to the dose delays for neutropenia and/or its complications.
UFT is composed of uracil and tegafur
(1-[2-tetrahydrofuryl]-5-fluorouracil) in a molar ratio of 4:1. In
one double-blind, randomized study of this agent, 56 evaluable
patients with advanced breast cancer received either UFT at a dose of
400 mg/day or tegafur at a dose of 800 mg/day. Although no
statistically significant difference in response rate was detected
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/day
and calcium folinate 90 mg/day (days 7 to 21) with carboplatin
(Paraplatin) 100 mg/m²/day (days 1 to 3) and etoposide (VePesid)
100 mg/m²/day (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 to compare the activity of UFT at a dose of
350 mg/m²/day from day 1 to day 14 vs 5-FU 500 mg/m²/day on
day 1 and day 8, both in combination with doxorubicin (Adriamycin) 50
mg/m² and cyclophosphamide (Cytoxan) 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%), and median
response duration was 16 weeks in both arms. Toxicity was low with
Vinorelbine has been combined in a continuous infusion with 5-FU or
with 5-FU plus calcium folinate. In first-line treatment of
metastatic breast cancer, vinorelbine (30 mg/m² on days 1 and 5)
in combination 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. A second-line therapy of vinorelbine (30 mg/m²
on day 1) plus 5-FU (750 mg/m²/day in a continuous infusion
from 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/week starting doses were not maintained throughout
treatment. In a phase II pilot study by Mardiak et al, 15
previously untreated patients receiving vinorelbine (20 mg/m² on
days 1 and 8) in combination with 5-FU (500 mg/m² on days 1 and
8) and calcium folinate (200 mg/m² on days 1 and 8) for
metastatic breast cancer experienced a 73% (11 of 15 patients)
overall response rate.
Thus, given the need for new, effective, non-anthracycline,
non-taxanebased chemotherapies for metastatic breast cancer,
and based on the significant single-agent clinical activities of
vinorelbine and UFT plus oral calcium folinate, a nonrandomized,
phase I, dose-escalating study of their combination was planned. The
primary objectives of the study were to determine the maximum
tolerated dose, dose-limiting toxicity, and recommended doses of UFT
and vinorelbine for the treatment of metastatic breast cancer in
patients who had previously received one chemotherapy regimen. In
addition, the pharmacokinetics of UFT and vinorelbine when used in
combination were also evaluated.
Patients and Eligibility Criteria
Women aged ³ 18 years with metastatic
breast cancer were accrued into this phase I, dose-finding study
conducted at two 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 were 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 ³ 100× 109/L,
serum creatinine £ 1.5 × upper
limit of normal (ULN), aspartate transaminase and alanine
transaminase £ 2 × ULN, and
bilirubin £ 1.25 × ULN. Patients
previously treated with a vinca alkaloid or continuous infusion 5-FU,
either in the adjuvant or metastatic setting, were ineligible.
Starting doses for the combination regimen 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/day, plus a fixed calcium folinate dose of 90
mg/day, both in three divided daily doses on days 1 through 21.
Vinorelbine was injected on days 8 and 15, provided the ANC was
greater than 1.5 × 109/L and/or platelet count was
greater than 75 × 109/L on those days. Treatment
cycles were repeated every 28 days, provided blood cell counts had
recovered and nonhematologic toxicity had resolved to grade £
1. Treatment could be delayed as long as 2 weeks if ANC remained <
1.5 ×109/L and/or platelets < 75 × 109/L.
The prophylactic use of 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 entry of the first patient and the next two
patients. Intraindividual dose escalation was not permitted. If one
of three patients at a 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 were then restarted for the subsequent cycle at the next lower
Doses that had been reduced for toxicity in individual patients could
not be re-escalated.
Dose-Limiting Toxicity and Maximum Tolerated Dose
Toxicity was graded according to the National Cancer Institute Common
Toxicity Criteria (NCI-CTC). 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 grade 3/4
nonhematologic toxicity (with the exception of alopecia and fatigue);
4) inability of patients to take full UFT doses for ³
3 of 21 days; 5) delay in start of second cycle (day > 29); and 6)
inability to take one of the three vinorelbine doses 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
Treatment Administration Guidelines
UFT was administered orally in three divided daily doses. Vinorelbine
was administered as a 5-minute intravenous infusion.
The sequence for cycle 1, days 1, 8, and 15, was UFT first dose 7:00
am; vinorelbine 6 hours after (1:00 pm); UFT second dose 3:00 pm; and
UFT third dose 11:00 pm.
The sequence for cycle 2, days 1, 8, and 15, was vinorelbine first
dose 7:00 am; UFT first dose 7:10 am; UFT second dose 3:10 pm; and
UFT third dose 11:10 pm.
For the subsequent cycles, the sequence for days 1, 8, and 15 was UFT
first dose 7:00 am; vinorelbine at the investigators discretion
after the first dose of UFT; UFT second dose 3:00 pm; and UFT third
dose 11:00 pm.
Treatment was continued unless there was evidence of disease
progression, unacceptable toxicity, or patient refusal.
Pretreatment evaluations included medical history; physical
examination and vital signs; WHO performance status; left ventricular
ejection fraction; tumor measurements (chest x-ray, abdominal
computed tomography [CT] scan, or ultrasound and CT scans of all
measurable and/or evaluable lesions); complete blood cell count
(white blood cells, platelets, hemoglobin); blood biochemistry and
urinalysis; liver function tests; and electrocardiogram. During
treatment, hematologic measurements were performed twice weekly. To
assess response, tumor measurements were repeated every two cycles,
or every cycle, if clinically indicated.
Patients who had received at least two cycles of therapy were
evaluable for response to treatment according to standard WHO
criteria unless disease progression was noted prior to cycle 2,
in which case, treatment was considered to have failed.
The pharmacokinetics of UFT and vinorelbine were evaluated during the
first treatment cycle. For UFT, blood samples were collected before
the first dose on day 1, then 30 minutes and 1, 1.5, 2, 2.5, 4, and 6
hours after the first dose. In addition, samples were collected on
days 8, 15, and 21 as follows: before the first daily dose, then 30
minutes and 1, 1.5, 2, and 6 hours after this dose. For vinorelbine,
blood samples were collected on day 1 immediately before the 5-minute
infusion that was administered 6 hours after the first dose of UFT,
then 5, 10, 20, 35 minutes, 1:35, 3:35, 6:35, 10:35, and 18 hours
after the start of infusion.
The pharmacokinetics of UFT were also evaluated during the second
treatment cycle. Vinorelbine was infused first, 10 minutes before
UFT. Blood samples were collected at day 1 before the first dose, and
30 minutes and 1, 1.5, 2, 2.5, 4, and 6 hours after this first dose.
In addition, samples were collected on days 8, 15, and 21 before the
first daily dose, then 30 minutes and 1, 1.5, 2, and 6 hours after
For both drugs, the analysis focused on the area under the plasma
concentration-time curve (AUC) and total plasma clearance. The
half-lives (t½a, t½b,
t½g) and volume of
distribution at steady state (Vss)
were also estimated.
Patient Characteristics and Treatment Administration
As of September 1, 1998, nine patients (age 48 to 70 years) have been
treated with UFT plus vinorelbine as second-line cytotoxic therapy
for metastatic breast cancer, at dose levels 1 and 2 (Table
2). Five patients had a WHO performance status of 0, and three
had a WHO performance status of 1. Five of nine patients had liver metastases.
Because of one patient with dose-limiting toxicity, six patients were
treated at dose level 1. Level 2, with three patients enrolled and
one patient with dose-limiting toxicity, is currently being studied.
A total of 18 cycles of UFT/vinorelbine have been administered. At
level 1, because of progressive disease, five patients have received
only two cycles; although the last patient has received six cycles.
Thus far, no grade 3/4 episodes of hematologic toxicity have been
observed. One patient at each dose level, however, was unable to take
one of the three vinorelbine doses because of grade 2 neutropenia at
day 15 (dose-limiting toxicity).
No grade 3/4 nonhematologic toxicities have been observed. Table
3 illustrates the overall incidence of grade 1/2 nonhematologic
toxicities, including nausea/vomiting, diarrhea, constipation,
hand/foot syndrome, fatigue, and stomatitis.
The pharmacokinetics of UFT and vinorelbine were evaluated in the six
patients enrolled at level 1. For the AUC0-6h of 5-FU,
uracil, and tegafur, the results are shown in Table
4. For the patient who developed a dose-limiting toxicity at day
15 (inability to give the vinorelbine dose because of grade 2
neutropenia), the AUC0-6h of 5-FU and uracil were significantly
higher (P < .01) than noted for the other patients. The
vinorelbine pharmacokinetic values are reported in Table
5 for these five patients.
The six patients at level 1 were evaluable for antitumor response.
One had a partial response in liver metastasis. The remaining five
patients experienced disease progression after two cycles.
We report the very preliminary results of an ongoing study that is
currently enrolling patients at dose level 2. Two patients with
dose-limiting toxicity have been observed: one patient at each dose
level was unable to receive one of the three vinorelbine doses
because of grade 2 neutropenia at day 15. The pharmacokinetic study
involving the six patients at level 1 has indicated a significant
increase at day 15 of AUC0-6h of 5-FU and uracil for the
patient with dose-limiting toxicity.
1. Valagusa P, Bonadonna G, Veronesi A: Patterns of relapse and
survival following radical mastectomy. Cancer 41:1170-1178, 1978.
2. Fisher B, Slack N, Katrych D, et al: Ten-year follow-up results of
patients with carcinoma of the breast in a cooperative clinical trial
evaluating surgical adjuvant chemotherapy. Surg Gynecol Obstet
3. Early Breast Cancer Trialists Collaborative Group. Systemic
treatment of early breast cancer by hormonal, cytotoxic, or immune
therapy. Lancet 339:1-15, 1992.
4. Henderson IC: Chemotherapy of breast cancer. Cancer 51:2553-2559, 1983.
5. Henderson IC: Chemotherapy for metastatic disease of breast
cancer, in Harris J, Hellman S, Henderson IC, Kinne DW (eds): Breast
Disease, 2nd ed, pp 604-605. Philadelphia, JB Lippincott Co, 1991.
6. Marty M, Extra JM, Dieras V, et al: A review of the antitumor
activity of vinorelbine in breast cancer. Drugs 44(suppl 4):29-35, 1992.
7. Rothenberg ML: Taxol, Taxotere, and other new taxanes. Curr Opin
Invest Drugs 2:1269-1277, 1993.
8. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion
in combination with bolus doxorubicin in women with untreated
metastatic breast cancer: High anti-tumor efficacy and cardiac
effects in a dose-finding and sequence-finding study. J Clin Oncol
9. Misset JL, Dieras V, Bozec L, et al: Long-term follow-up of the
phase I/II study of docetaxel and doxorubicin as 1st-line CT of
metastatic breast cancer (abstract 613). Proc Am Soc Clin Oncol
10. Henderson IC, Berry D, Demetri G, et al: Improved disease-free
survival and overall survival from the addition of sequential
paclitaxel but not from the escalation of doxorubicin dose level in
the adjuvant chemotherapy of patients with node-positive primary
breast cancer (abstract 390a). Proc Am Soc Clin Oncol 17:101a, 1998.
11. Cros S, Wright M, Morimoto M, et al: Experimental antitumor
activity of Navelbine. Semin Oncol 16(suppl 4):15-20, 1989.
12. Toso C, Lindley C: Vinorelbine: A novel vinca alkaloid. Am J
Health-Syst Pharm 52:1287-1304, 1995.
13. Potier P: The synthesis of Navelbine, prototype of a new series
of vinblastine derivatives. Semin Oncol 6(suppl 4):2-4, 1989.
14. Binet S, Fellous A, Lataste H, et al: In situ analysis of the
action of Navelbine on various types of microtubules using
immunofluorescence. Semin Oncol 16(suppl 4):5-8, 1989.
15. Canobbio L, Boccardo F, Pastorino G, et al: Phase II study of
Navelbine in advanced breast cancer. Semin Oncol 16(suppl 4):33-36, 1989.
16. Bruno S, Lira-Puerto V, Texeira L, et al: Phase II trial with
vinorelbine (Navelbine) in the treatment of advanced breast cancer
(abstract). Ann Oncol 3(suppl 1):126, 1992.
17. Garcia-Conde J, Lluch A, Casado A, et al: Phase II trial with
Navelbine in advanced breast cancer previously untreated (abstract
52). Breast Cancer Res Treat 23:142, 1992.
18. Fumoleau P, Delgado FM, Delozier T, et al: Phase II trial of
weekly intravenous vinorelbine in first-line advanced breast cancer
chemotherapy. J Clin Oncol 11:1245-1252, 1993.
19. Weber B, Vogel C, Jones S, et al: A US multicenter phase II trial
of Navelbine in advanced breast cancer (abstract 46). Proc Am Soc
Clin Oncol 12:61, 1993.
20. Romero A, Rabinovich MG, Vallejo CT, et al: Vinorelbine as
first-line chemotherapy for metastatic breast cancer. J Clin Oncol
21. Marty M, Leandri S, Extra JM, et al: A phase II study of
vinorelbine in patients with advanced breast cancer (abstract 1017).
Proc Am Assoc Cancer Res 30:256, 1989.
22. Tresca P, Fumoleau P, Roche H, et al: Vinorelbine, an active new
drug in breast carcinoma: Results of an ARTAC phase II trial
(abstract 18). Proc 13th San Antonio Br Cancer Symp 16:149-162, 1990.
23. Gasparini G, Caffo O, Barni S, et al: Vinorelbine is an active
antiproliferative agent in pretreated advanced breast cancer
patients: A phase II study. J Clin Oncol 12:2094-2101, 1994.
24. Hortobagyi GN: Future directions for vinorelbine (Navelbine)
Semin Oncol 22(suppl 5):80-87, 1995.
25. Tashiro H, Nomura Y, Ohsaki A: A double-blind comparative study
of tegafur (FT) and UFT (a combination of tegafur and uracil) in
advanced breast cancer. Jpn J Clin Oncol 24:212-217, 1994.
26. Daniels M, Diaz-Rubio E, Guillem V, et al: Phase II trial of UFT
activity in pretreated breast cancer. J Clin Oncol 23:363-365, 1993.
27. Villalon AH, DeGuzman LB, Samson MC, et al: A randomized trial of
oral UFT (tegafur + uracil) and 5-fluorouracil in combination with
cyclophosphamide and doxorubicin in the treatment of advanced cancer
at Philippine General Hospital (abstract 691). Proc Am Soc Clin Oncol
28. Dieras V, Extra JM, Bellissant E, et al: Efficacy and tolerance
of vinorelbine and fluorouracil combination as first-line
chemotherapy of advanced breast cancer: Results of a phase II study
using a sequential group method. J Clin Oncol 14:3097-3104, 1996.
29. Vogel C, Hochster H, Blumenreich M, et al: A US multicenter phase
II study of IV Navelbine (NVB) and 5-fluorouracil (5-FU) as
first-line treatment of patients with advanced breast cancer
(abstract 62). Proc Am Soc Clin Oncol 14:91, 1995.
30. Fumoleau P, Delozier T, Extra JM, et al: Vinorelbine (Navelbine)
in the treatment of breast cancer: The European experience. Semin
Oncol 22(suppl 5):22-29, 1995.
31. Mardiak J, Bohanicky C, Salek J, et al: Vinorelbine,
5-fluorouracil (5-FU) and leucovorin (LV) in advanced breast cancer:
A pilot phase II study. Proc 5th Intern Congress on Anti-Cancer
Chemother 605, 1995.
32. WHO Handbook for Reporting Results of Cancer Treatment. World
Health Organization, Geneva, 1979.