A phase I/II study of high-dose 5-fluorouracil/folinic acid (5-FU/FA),
given weekly for six weeks by 24-hour infusion, demonstrated high efficacy,
with a response rate of 41% (13 of 32 patients), and low toxicity in intensively
pretreated patients with metastatic breast cancer. Based on these results,
we added paclitaxel (Taxol) to the regimen in a second phase I/II study,
also in pretreated patients with metastatic breast cancer. The combination
of paclitaxel with weekly high-dose infusional 5-FU/FA was well tolerated
and highly effective (response rate, 59%; 32 of 54 patients) in these patients,
including those with anthracycline-refractory disease. In an ongoing phase
II study, we intend to estimate the value of adding cisplatin to this regimen
as first-line treatment of metastatic breast cancer to create an effective
treatment for patients who have received anthracyclines in the adjuvant
In June 1995, we initiated this phase II study of first-line treatment
in patients with metastatic breast cancer and no prior chemotherapy for
All patients had histologically proven breast cancer; were pretreated
with chemotherapy only in the adjuvant setting; had not had any chemotherapy
for metastatic disease; had bidimensionally measurable disease with or
without evaluable disease (ie, bone metastases); and had adequate hematologic,
renal, and hepatic function, as well as no severe, uncontrolled comorbidities.
Additional eligibility criteria included an Eastern Cooperative Oncology
Group performance status of 0, 1, or 2; life expectancy of at least 3 months;
and age 18 or more years. Pregnancy was excluded prior to study entry.
All patients gave informed consent before participating in this study,
which was approved by the institutional review board. A quality-of-life
analysis was performed throughout the study and during follow-up.
At this time, 28 patients have entered this ongoing phase II study.
Patients had progressive disease and/or tumor-related symptoms prior to
study treatment. All patients had at least one bidimensionally measurable
tumor site. The characteristics of the patients treated are outlined in
Patients were treated with high-dose 5-FU 2.0 g/m² (by 24-hour
infusion) plus FA 500 mg/m² (by 2-hour infusion prior to 5-FU) weekly
for 6 weeks (days 1, 8, 15, 22, 29, and 36). Cisplatin 50 mg/m² (by
1-hour infusion) was administered on days 1 and 22, and paclitaxel 175
mg/m² (by 3-hour infusion) was given on days 0 and 21 after standard
premedication with corticosteroids and H1- and H2-receptor
antagonists. Each cycle comprised 6 weeks, followed by 2 weeks of rest,
with a total of three cycles planned. All patients were treated under outpatient
conditions using intravenous port systems and portable pumps (Figure
Mode of Administration/ Drug Therapy
All patients had intravenous port systems. Folinic acid 500 mg/m²
was dissolved in 500 mL of a 0.9% saline solution and given over 2 hours
as a continuous infusion, prior to a 24-hour continuous infusion of 5-FU
(2 g/m²), given by portable pump. This application was performed weekly
for 6 weeks. Cisplatin 50 mg/m² was given on days 1 and 22, and paclitaxel
at a dose of 175 mg/m² was given on days 0 and 21. We used standard
premedication with corticosteroids and H1- and H2-receptor
antagonists, as well as polyvinyl chloride-free infusion material and filter
systems for paclitaxel administration. Cisplatin and paclitaxel, dissolved
in 1,000 mL of 0.9% saline solution, were given prior to the FA/5-FU. While
the number of applied cycles depended on response and toxicity, three full
cycles were planned for patients without tumor progression and without
worsening of performance status or tumor-related symptoms during chemotherapy.
Cytokines were not administered.
The 5-FU dosage was reduced by 20% in cases of mucositis or stomatitis
or of diarrhea greater than World Health Organization (WHO) stage 2. If
mucositis, stomatitis, or diarrhea greater than WHO stage 2 were present
on the day of planned treatment, chemotherapy was delayed until full recovery
from side effects and the dose of 5-FU was reduced by 20% for the remaining
Prior to treatment, all patients underwent physical examination, chest
x-ray, abdominal ultrasound, thoracic and/or abdominal computed tomography
scan if indicated, bone scan, blood cell counts, routine biochemical tests,
and tumor-marker screening. Tumor response was evaluated after each treatment
cycle, using those techniques required to assess tumor locations present
at study entry. Full restaging was done following induction of an objective
response, upon progressive disease assumed due to contradictory results
between imaging techniques and biochemical tests, upon worsening of performance
status or clinical symptoms despite tumor regression or stable disease,
and at the end of treatment.
Blood cell counts and assessment of toxicities were done weekly during
treatment, prior to each treatment period, and after the last chemotherapy
cycle. Biochemical parameters and tumor markers were measured after each
treatment cycle. Quality-of-life assessment was performed thoughout the
treatment period and during follow-up, using the European Organization
for Research and Treatment of Cancer quality-of-life scale. Toxicity was
graded according to the WHO scale.
Response Criteria/Statistical Analysis
Response guidelines were performed according to standard WHO criteria:
Tumor response was documented in two evaluations performed at least 6 weeks
apart. Complete remission and partial remission response duration were
calculated from the date the response was first documented. Survival and
time to progression were computed actuarially, using the Kaplan-Meier method,
beginning with the date the patient was placed on study. Duration of response
also was calculated according to Kaplan-Meier, from the date of response
to the date of progressive disease.
With a total of 65 treatment cycles and a median of two treatment cycles
per patient (range, one to three cycles), all 28 patients were evaluable
for toxicity. No serious acute hypersensitivity reactions were attributed
to paclitaxel. Neutropenia was common but moderate in most patients (WHO
grade 3 in 35% of cycles). No hospitalizations were necessary for febrile
neutropenia. The duration of grade 3 and 4 neutropenia was generally brief.
No cytokines were used. Aside from common total alopecia, nonhematologic
toxicities consisted primarily of moderate (defined as WHO grade 2 in percent
of cycles) myalgia (45%), diarrhea (53%), mucositis (39%), nausea and vomiting
(52%), and hand-foot syndrome (51%). Peripheral polyneuropathy was cumulative
and occurred most frequently during the third treatment cycle, with mild-to-moderate
expression. World Health Organization grade 3 toxicity occurred in 7% of
cycles as nausea and vomiting and in 11% of cycles as diarrhea.
The following results have been achieved: 25% (7 of 28) of patients
have attained a complete remission and 57% (16 of 28) a partial remission;
11% (3 of 28) have stable disease, and 7% (2 of 28) have progressive disease.
Overall response rate was 83% (95% confidence interval, 66% to 100%) (Table
2). Median time to maximum response was 2 months (range, 1 to 5), median
remission duration was 8 months (range, 4 to 22). Eight of the 28 patients
are still receiving treatment, and the median survival time has not yet
Sledge and coworkers summarized cisplatin as a significant, active
single agent for the first-line treatment of metastatic breast cancer.
Additionally, preclinical data suggest a synergistic interaction for combining
cisplatin with either paclitaxel or 5-FU.[5,6] Further, our own clinical
toxicity data of combination paclitaxel plus high-dose 5-FU/FA allows the
addition of a third combination partner for use in a less-pretreated patient
The preliminary results of this ongoing phase II study of weekly high-dose,
24-hour infusional 5-FU/FA with paclitaxel/cisplatin indicate an active
outpatient combination regimen for
first-line treatment of women with metastatic breast cancer. In this study,
we will further estimate the value of this regimen with respect to response
duration, survival, toxicity, and quality of life during and after treatment.
This active combination could have an impact on the management of metastatic
breast cancer because of the more frequent use of anthracyclines and high-dose
chemotherapy with peripheral stem cell support in the adjuvant setting.
1. Wilke H, Klaassen U, Achterrath W, et al: Phase I/II study with a
weekly 24-hour infusion of 5-fluorouracil plus high dose folinic acid (HD
5-FU/FA) in intensively pretreated patients with metastatic breast cancer.
Ann Oncol 7:55-58, 1996.
2. Klaassen U, Wilke H, Phillippou Pari C, et al: Phase I/II study with
paclitaxel in combination with weekly high dose 5-fluorouracil/folinic
acid (HD 5-FU/FA) in the treatment of metastatic breast cancer. Semin
Oncol 22(suppl 14):7-11, 1995.
3. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations.
J Am Stat Assoc 53:457-481, 1958.
4. Sledge J, Loehrer PJ, Roth BJ, et al: Cisplatin as first-line therapy
for metastatic breast cancer. J Clin Oncol 6:1811-1814, 1988.
5. Vanhoefer U, Harstrick A, Wilke H, et al: Schedule-dependent antagonism
of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell
lines in vitro. Eur J Cancer 31A:92-97, 1995.
6. Klaassen U, Harstrick A, Schleucher N, et al: Activity and schedule-dependent
interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide in cisplatin-sensitive
and -refractory human ovarian carcinoma cell lines. Br J Cancer