Continuous-infusion 5-fluorouracil (5-FU) is
not a new therapeutic concept. The clinical use of long-term
infusional fluorinated pyrimidines was first described in the
1960s, but interest has been renewed in recent years as the
limitations of conventional chemotherapy in common solid tumors have
become increasingly clear. 5-FU has been the major drug studied.
Treatment of advanced breast cancer with continuous-infusion 5-FU has
been evaluated in several small phase II studies, usually involving
heavily pretreated patients. In a review of these studies, Cameron et
al cite an overall objective response rate of 29% among the 199
patients treated with 5-FU doses of 200 to 300 mg/m²; some of
these patients previously had received conventional 5-FU therapy.
There was considerable variation between studies in response rates,
including one report of a 54% response.
More recently, a Swiss group reported their findings from a larger,
retrospective analysis of 106 consecutive patients treated on an
outpatient basis with 5-FU infused at 250 mg/m² every 24 hours
for 3 weeks, followed by a 1-week pause. In this group, 21% of 80
evaluable patients achieved an objective response, including a 20%
response rate among patients previously treated with conventional
administration of 5-FU. Interestingly, the authors also reported
subjective symptom improvement in 44% of 104 patients evaluable for
this endpoint, and in general treatment was well tolerated. These
results highlight the potential value of continuous 5-FU infusion as
palliative therapy and hint at activity as first-line treatment,
although no phase II trial data have been reported.
Based on this evidence of high activity in metastatic breast cancer
associated with continuous infusion of 5-FU, at the Royal Marsden
Hospital we have attempted to expand on these results by combining
continuous-infusion 5-FU with other chemotherapeutic agents with
known activity against this disease. Our experiences are reported here.
At the Royal Marsden Hospital, we have some experience with 5-FU
delivered by ambulatory pump and Hickman line. When administered to
patients with metastatic or locally advanced breast cancer at a
dosage of 200 mg/m²/day for up to 6 months, in combination with
bolus epirubicin 60 mg/m² intravenously and cisplatin 60
mg/m² intravenously given every 3 weeks (ECisF), we observed an
overall response rate of 84%, including a complete clinical remission
rate of 36% in locally advanced disease.
In a subsequent phase II trial, we used the same regimen as that for
preoperative/neoadjuvant chemotherapy for patients with early
operable breast cancer (tumor size ³
3 cm). An overall response rate of 98% and a complete clinical
remission rate of 66% were observed among the 50 patients included in
the study. We have since incorporated this treatment into a
randomized trial (see below) involving 123 patients. Combined results
from these two reports indicate an objective response rate of 96%,
complete clinical remission among 57%, and an actuarial 5-year
survival rate of 75%. These findings warranted further investigation.
There are two national, multicenter, randomized trials of infusional
chemotherapy ongoing at the Royal Marsden Hospital. In the
firstTrial of Primary Infusional Chemotherapy
(TOPIC)patients with tumors ³ 3
cm in maximum diameter are randomized to preoperative chemotherapy
with infusion ECisF vs conventional AC (Adriamycin [doxorubicin] 60
mg/m², cyclophosphamide 600 mg/m² intravenously every 3
weeks for six courses). To date, 402 patients have been entered.
In the Trial of Adjuvant 5-FU Infusional Chemotherapy (TRAFIC), the
efficacy of adjuvant therapy with infusional ECisF is being compared
with that of standard conventional FEC (5-FU 600 mg/m²,
epirubicin 60 mg/m², cyclophosphamide 600 mg/m² every 3
weeks for six courses). This trial opened recently, and so far 202
patients have been entered. Participating centers for these trials
are listed in Table 1.
Is Cyclophosphamide Better?
One of the disadvantages of the ECisF regimen is the extended
duration of drug administration. The use of cisplatin in ECisF
necessitates prolonged outpatient or overnight inpatient
administration because of the need for intravenous hydration. In
addition, cisplatin is associated with a greater risk of emesis,
renal impairment, neurotoxicity, and high-tone hearing loss than
other standard cytotoxic agents used in the treatment of breast cancer.
Cyclophosphamide has a long track record in the treatment of breast
cancer, both as a single agent and in combination with 5-FU and
Adriamycin (doxorubicin) (FAC), or 5-FU and epirubicin (FEC).
Cyclophosphamide has a number of practical advantages over cisplatin:
it may be given readily on an outpatient basis, nonhematologic
toxicities are minor, and it does not require careful monitoring of
renal function during treatment. These features may provide the
combination regimen of infusional 5-FU, epirubicin, and
cyclophosphamide (ECycloF) with some advantages over the same current
standard regimen with cisplatin. Therefore, we recently performed a
randomized phase II study to evaluate the safety and efficacy of
continuous infusion of ECycloF vs ECisF in a 2:1 randomization.
Ninety-six women (median age, 49 years; range, 28 to 73) with breast
cancer (59 metastatic, 37 locally advanced) received 200
mg/m²/day of 5-FU by continuous infusion (Hickman line) and six
cycles of epirubicin (60 mg/m² every 21 days) plus either
cyclophosphamide 600 mg/m² every 21 days (38 metastatic, 24
locally advanced) or cisplatin 60 mg/m² every 21 days (21
metastatic, 13 locally advanced). There were no significant
differences in patient characteristics between these two groups.
ECycloF was better tolerated than ECisF in terms of lethargy (P =
.005), stomatitis (P = .008), plantar-palmar erythema (P = .02),
constipation (P < .001), thrombosis (P = .0014), and nausea and
vomiting (P = .005). Although there was a trend toward more anemia
and leukopenia with ECisF (P = .01), there was no significant
difference in the rates of infection. Comparable efficacy was evident
in overall response rates (69% vs 68%), complete response rates (13%
vs 15%), and median progression-free survival (9 vs 8 months) for
ECycloF vs ECisF, respectively.
In conclusion, this study indicated that ECycloF was a simple
outpatient regimen with a lower incidence of severe nonhematologic
toxicity than inpatient ECisF. In addition, it had comparable
efficacy and was considerably more economical. Although the results
of this phase II trial should not be interpreted in the same manner
as those of a phase III study, we addressed the major sources of
variability in phase II trials.
We selected a randomized trial design to reduce the risk of selection
bias in interpreting efficacy and to allow a valid comparison of
toxicity and side effects for ECycloF vs the infusional ECisF
control, using standard World Health Organization criteria. On
this basis we feel comfortable suggesting that cyclophosphamide be
substituted for cisplatin in future trials of infusional 5-FU
combination chemotherapy in the treatment of breast cancer.
Replacing 5-FU With UFT/Calcium Folinate
The major disadvantage of infusional 5-FU is that it involves the use
of ambulatory pumps with Hickman lines, which is resource intensive
and inconvenient for patients. Complications of ambulatory infusions
include central venous thrombosis, chemical phlebitis, pneumothorax,
and infections, at rates as high as 13%. An oral 5-FU preparation
with pharmacokinetics and efficacy similar to those of
continuous-infusion 5-FU would offer an important advantage in terms
of resource utilization and ease of administration.
UFT (uracil plus tegafur in a 4:1 molar ratio) plus oral calcium
folinate is combined in a compound called Orzel. It has a selective
antineoplastic effect due to biochemical modulation by uracil, which
enhances 5-FU concentration more specifically within tumor tissues
than within normal tissues. UFT plus oral calcium folinate also has
fewer side effects than other agents of the fluorinated pyrimidine series.
Data from in vivo studies conducted in Japan suggest that UFT plus
oral calcium folinate and tegafur distribute 5-FU comparably in blood
and other normal tissues, but UFT plus oral calcium folinate results
in five to 10 times greater distribution of 5-FU in tumors. In 3- to
9-month chronic toxicity studies, UFT plus oral calcium folinate
produced no greater toxicity than did 5-FU.
Clinical phase I and II studies described elsewhere in this
supplement have shown that UFT plus oral calcium folinate is
relatively well tolerated (dose-limiting toxicities in phase I
studies were leukopenia, thrombocytopenia, nausea, vomiting,
diarrhea, stomatitis, mucositis, fever, and fatigue), and has
activity in gastrointestinal and breast carcinomas. Furthermore, its
clinical and pharmacokinetic activity is comparable to that of
intravenously administered 5-FU when each is combined with calcium folinate.
The recommended phase II dose on a 28-day schedule with a 2-week rest
period is 200 mg/m²/day of UFT with 90 mg of calcium folinate.
UFT plus oral calcium folinate is therefore an orally available agent
with a favorable side-effect profile and efficacy that should compare
well with that of conventional regimens.
We are therefore carrying out a nonrandomized, single-center,
open-label, dose-escalation study of epirubicin, cyclophosphamide,
and UFT plus oral calcium folinate (ECO) in the treatment of patients
with locally advanced/metastatic breast cancer. The primary objective
of this study is to determine the maximum tolerated dose and the
testing for phase II of this regimen. Secondary objectives include
determining side effects, dose-limiting toxicities, response rate,
and time to progression. We also plan to measure tumor-related
symptom relief. The schedule is outlined in Table
The dose escalation will be carried out in cohorts with at least six
patients in each cohort, as outlined in Table
The maximum tolerated dose for UFT plus oral calcium folinate in
combination with epirubicin and cyclophosphamide will be defined as
the dose level at which a dose-limiting toxicity occurs in three or
more of the first six patients, or six or more of 12 patients in a
given cohort. Once the maximum tolerated dose is defined, additional
patients will be treated at the dose level below the maximum
tolerated dose. The number treated will be expanded to 20 patients to
better characterize the phase II dose and to allow assessment of
tumor response at the recommended dose.
The main inclusion criteria are locally advanced or metastatic breast
cancer in patients who have received either no prior chemotherapy or
adjuvant chemotherapy completed at least 12 months prior to study
entry; prior anthracycline treatment if the total dose was £
360 mg/m² or prior mitoxantrone treatment with a total
cumulative dose £ 66 mg/m² is
acceptable if this treatment was completed at least 12 months before
We have designed an open-label dose-escalation study to determine the
maximum tolerated dose and recommended phase II dose of the
combination of UFT plus oral calcium folinate, epirubicin, and
cyclophosphamide. The trial has received scientific and ethical
approval at the Royal Marsden Hospital. We will soon begin to enroll patients.
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