The combination of paclitaxel and 5-FU constitutes a promising
regimen that has been previously investigated in breast cancer
patients after treatment with anthracycline- and
alkylating-agentbased regimens. Response rates of 54% to 69%
have been reported for the combination of leucovorin/5-FU/paclitaxel
as salvage chemotherapy after prior exposure to mostly
anthracycline-containing regimens.[35,36] In one study of 20 patients
with anthracycline-refractory disease, a 55% overall response rate
and a median response duration of 8 months were achieved. In this
study, leucovorin 500 mg/m² was administered as an infusion
given over 2 hours prior to 5-FU and paclitaxel. 5-FU was given at a
dose of 2 g/m² over 24 hours and paclitaxel 175 mg/m² was
infused over 3 hours.
In a phase II trial of intravenous 5-FU, folinic acid,
paclitaxel, and cisplatin as a first-line treatment of metastatic
breast cancer, an overall response rate of 82% with only moderate
side effects was achieved. The high response rates observed in these
studies support the use of prolonged fluoropyrimidine in combination
The combination of paclitaxel and 5-FU has also been successfully
employed in the treatment of patients with gastrointestinal cancers.
In a phase II trial of 24-hour, continuous-infusion, high-dose 5-FU
given weekly in combination with short-infusion paclitaxel every
second week in patients with gastric cancer, partial remissions were
observed in 32% of patients. Further development of this regimen
includes alternating weekly doses of paclitaxel and cisplatin
combined with continuous 24-hour infusions of 5-FU. Activity has also
been reported for paclitaxel/5-FU combinations in patients with
esophageal cancer, and this regimenpossibly with the addition
of cisplatinmay also be used for neoadjuvant treatment of this disease.
A phase I trial of UFT and paclitaxel as a second-line treatment of
metastatic breast cancer has used a single infusion of paclitaxel at
a fixed dose of 175 mg/m² intravenously administered over 3
hours on day 1. UFT and oral leucovorin are given orally for 14 days
followed by a 1-week period without treatment. Therapy is repeated
every 21 days. UFT is escalated by 100 mg increments from a
total starting dose of 300 mg/d while leucovorin is given at a fixed
dose of 30 mg three times a day. Another phase I trial in breast
cancer is ongoing.
The current series takes the use of protracted 5-FU application
(given orally as UFT) in combination with paclitaxel one step
further, applying paclitaxel in a dose-dense and moderately toxic
weekly schedule. With 26 patients entered into this new protocol, it
is becoming clear that four weekly doses of paclitaxel can be given
in combination with full-dose UFT plus leucovorin. The major
toxicities appear to be gastrointestinal. One problem of the
protracted use of UFT plus leucovorin over 4 weeks might be that
gastrointestinal side effects will occur during the last week of oral treatment.
Thus, for future protocols, a shortened application schedule may be
preferable. However, the goal of this protocol is to establish the
maximum tolerated dose and to gain further information regarding
phase II data. Promising preliminary responses have been observed in
extensively pretreated patients and it is hoped that this study will
result in the definition of a tolerable and effective palliative
treatment regimen for patients with a variety of solid tumors.
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