The classic example of a cyclespecific,
S-phasedependent drug with a short half-life is 5-fluorouracil
(5-FU). Conventional bolus injection may not be the most effective
schedule. Recent phase II study results demonstrated high efficacy
and low toxicity for a weekly schedule of 24-hour infusional
5-FU/calcium folinate, as well as for continuous infusion of
low-dose 5-FU in intensively pretreated patients with metastatic
Paclitaxel (Taxol) in combination with weekly high-dose 5-FU/calcium
folinate constitutes a highly active salvage regimen for patients
with pretreated metastatic breast cancer. UFT (uracil and tegafur
in a 4:1 molar ratio) may allow administration of long-term, low-dose
oral 5-FU with a similar pharmacokinetic profile as a continuous
infusion, but without the need for central venous catheters and
portable pumps. We therefore initiated this ongoing phase I study in
which UFT was administered orally for 14 days with oral calcium
folinate (Orzel) in combination with paclitaxel as a 3-hour
intravenous infusion every 3 weeks. The data that follow were
presented at the April 1999 meeting of the American Association for
Patients in this study had to have histologically proven breast
cancer and a failure to respond to previous chemotherapy for breast
cancereither adjuvant, metastatic, or both. Other inclusion
criteria were progressive measurable or evaluable disease, age ³
18 years, World Health Organization (WHO) performance status £
2, life expectancy of ³ 3 months, and
adequate renal, liver, and bone marrow function (creatinine,
bilirubin £ 1.5 × upper limit of
normal and absolute neutrophil count [ANC] ³
2.0 × 109/L, platelet count ³
100 × 109/L). All patients gave informed consent
prior to study entry.
Staging and Follow-Up
Prior to treatment, all patients underwent complete medical history
and physical examination, electrocardiogram, determination and
measurements of study parameters by chest x-ray, bone scan, and
computed tomography scan and/or ultrasound. During treatment, full
hematologic blood counts, determination of liver and renal functions,
and assessment of nonhematologic toxicities were performed weekly.
Response to treatment was assessed prior to each cycle. The standard
WHO common toxicity criteria were used to evaluate response and toxicity.
After standard premedication with dexamethasone (8 mg orally 12 h and
6 h prior to each paclitaxel infusion), cimetidine (Tagamet) (400 mg
intravenously), and clemastine (Tavist) (2 mg IV) 30 minutes before
each paclitaxel treatment, patients received paclitaxel, diluted in
1,000 mL 0.9% saline solution as a 3-hour IV infusion on day 1.
Concomitantly, UFT plus oral calcium folinate was started at day 1
and continued through day 14 in three divided daily doses. The dosage
administered at each dose level is described in Table
1. Cycles were repeated on day 21. Prophylactic antiemetic
treatment was given according to routine practice.
The starting UFT dose was 300 mg/day orally for 14 days (Table
1). A fixed 30-mg dose of calcium folinate was given orally
concurrently with each UFT dose at all dose levels. (Dosing may be
repeated after a 7-day rest period or on full recovery from any toxicity.)
We performed no intrapatient dose escalation. At least three patients
were treated at each dose level. If none of these patients developed
a dose-limiting toxicity during the first course of treatment, the
next dose level was opened. Dose-limiting toxicities were defined as
hematologic toxicity: ANC < 0.5 × 109/L for
> 7 days, ANC < 0.1 × 109/L for > 3 days,
any episode of febrile neutropenia, platelets < 25 × 109/L,
bleeding, absence of recovery of absolute neutrophil count and/or
platelets by day 35;
nonhematologic toxicity: any toxicity of common toxicity
criteria grade ³ 3 (excluding
alopecia, nausea and vomiting, myalgia, asthenia grade 3),
persistence of toxicity of common toxicity criteria grade ³
2 at day 35 (excluding alopecia, nausea and vomiting, myalgia,
asthenia grade 2), and inability to take ³
75% of planned UFT dose.
If one of the first three patients developed a dose-limiting
toxicity, a maximum of three additional patients were treated at this
dose level. If none or only one of these three additional patients
developed dose-limiting toxicity, the next dose level was opened. The
maximum tolerated dose was reached if three of six patients at a
given dose level developed dose-limiting toxicities during any course
of treatment. The recommended dose for phase II will be one dose
level below the maximum tolerated dose.
To date, 20 patients with pretreated metastatic breast cancer have
been entered in the trial. Median age is 52 years (range 28 to 70
years). Median performance status according to WHO criteria is 1
(range 0 to 1). All included patients have had prior chemotherapy
either as adjuvant treatment, for metastatic disease, or both. Four
of the 20 patients had anthracycline-refractory disease, defined as
disease progression while receiving anthracycline-containing
chemotherapy prior to study entry.
The observed toxicity at each dose level is outlined in Table
2. All patients experienced common toxicity criteria grade 3
alopecia. No dose-limiting toxicities were seen in 14 patients
treated at dose levels 1 to 3 (72 treatment cycles). In the fourth
dose level, one of three patients experienced a dose-limiting
toxicity as neutropenic fever. According to the protocol, an
additional three patients were entered at this dose level; these
patients did not experience a dose-limiting toxicity. WHO grades 1
and 2 peripheral neuropathy, arthralgia, and myalgia were common but
not dose-limiting. So far, no severe stomatitis or diarrhea has been
observed (Table 2).
All patients had disease progression, defined according to WHO
criteria, prior to study entry. Of the 20 enrolled patients, one has
had a complete remission, five have had partial remissions, five
minor remissions, and seven stable disease; only two patients
experienced progressive disease. Responses could be observed at all
dose levels (Table 3). An
improvement of tumor-related symptoms (pain, weight loss) was seen in
all patients with an objective tumor response as well as in patients
with stable disease. There has been good compliance among the
patients with the oral treatment regimen, as documented by a patient diary.
We have not reached the maximum tolerated dose of combination
paclitaxel and UFT plus oral calcium folinate within four dose levels
in this ongoing phase I study. We will continue the trial with dose
level 5 (paclitaxel 175 mg/m2 day 1 and UFT 700 mg total dose days 1
to 14 plus calcium folinate 90 mg days 1 to 14). Thus far,
preliminary data suggest that the combination of paclitaxel and UFT
plus oral calcium folinate is a convenient and effective regimen for
patients with pretreated metastatic breast cancer.
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weekly 24-hour infusion of 5-FU plus high-dose folinic acid in
intensively pretreated patients with metastatic breast cancer. Ann
Oncol 7:55-58, 1996.
2. Regazzoni S, Pesce G, Marini G, et al: Low-dose continuous
intravenous infusion of 5-fluorouracil for metastatic breast cancer.
Ann Oncol 7:807-813, 1996.
3. Klaassen U, Wilke H, Harstrick A, et al: Paclitaxel in combination
with weekly 24-hour infusional 5-fluorouracil plus leucovorin in the
second-line treatment of metastatic breast cancer: Results of a phase
II study. Ann Oncol 9:45-50, 1998.
4. 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.
5. Klaassen U, Ehricke S, Hilger R, et al: Phase I/II and
pharmacology study of paclitaxel plus oral UFT and leucovorin in the
second-line treatment of patients with metastatic breast cancer
(abstract 2187). Proc Am Assoc Cancer Res 39:320, 1999.