The overall prognosis for patients with
advanced breast cancer who failed a first chemotherapy attempt
remains poor. Currently, management with various combination-drug
regimens seems to be primarily palliative, producing objective
response rates of 20% to 40%. However, these regimens rarely cure and
are associated with considerable toxicity.
UFT, an antineoplastic agent containing uracil plus tegafur in a
molar ratio of 4:1, has demonstrated activity against colorectal,
head and neck, and breast cancers in previous studies.[1-3] In breast
cancer, response rates have ranged from 24% to 39%. This notable
single-agent activity has resulted in escalation of research into its
potential as therapy for breast cancer. UFT plus oral calcium
folinate (Orzel) as a biomodulator possesses activity similar to that
of intravenous 5-fluorouracil (5-FU) plus calcium folinate, with the
additional advantage of oral delivery. Based on this promising
background, we designed a phase II protocol to evaluate the
feasibility of using UFT plus oral calcium folinate to treat
extensively pretreated patients with advanced breast cancer.[4-8]
Between June 1997 and April 1998, 24 patients were entered in this
phase II tolerability study; only 18 patients were evaluable. Each
patient had been previously treated for advanced breast cancer with
chemotherapy or hormonal therapy. Prior regimens were based on the
anthracyclines, paclitaxel (Taxol), vinorelbine (Navelbine),
cyclophosphamide (Cytoxan), methotrexate, mitoxantrone (Novantrone),
mitomycin-C (Mutamycin), 5-FU, tamoxifen (Nolvadex), and
aminoglutethimide (Cytadren). The patient median age was 62 years
(range, 46 to 75 years); Eastern Cooperative Oncology Group (ECOG)
performance status was as follows: 0 in two patients; 1 in 14
patients, and 2 in eight patients (Table
Patients were treated with UFT plus oral calcium folinate according
to the following schema: 300 mg/m²/day of oral UFT plus 45
mg/day of oral calcium folinate administered every 12 hours for 28
days in cycles repeated every 35 days. Treatment history included UFT
plus oral calcium folinate as second-line treatment for three
patients (12.5%), as third-line treatment for 10 patients (41.7%), as
fourth-line treatment for seven patients (29.2%), and as fifth-line
treatment for four patients (16.7%).
A total of 63 cycles have been administered for a mean of three
cycles (range, one to 10 cycles) per patient. Based on this
follow-up, we have observed one complete response (5.6%) occurring in
soft tissue sites, and four partial responses (22.2%). The overall
response rate (complete response + partial response) was 27.8%.
Responses were noted in soft tissue, lung, and bone. Disease was
stable in eight patients (44.4%), and progressed in five patients (27.8%).
Compliance to treatment protocol was evaluated by means of a
patient-completed drug-intake log. Based on these documents,
compliance with the prescribed drug regimen appears to be reliable.
The toxicity of this regimen was generally mild to moderate (Table
2). Only one patient (5.56%) experienced grade 3 diarrhea during
the first drug treatment cycle, which did not recur after the UFT
dose was reduced to 250 mg/m²/day. Two patients presented with
grade 2 diarrhea (11.11%) and four patients with grade 1 diarrhea
(22.22%). Other observed toxicities included grade 2 abdominal pain
in one patient (5.56%), grade 2 mucositis in two patients (11.11%),
and grade 2 leukopenia in one patient (5.56%).
No patient required a treatment delay or withdrawal due to intolerance.
Based on our early results, oral administration of UFT plus oral
calcium folinate appears to be easily administered and associated
with low toxicity. In this study, a UFT plus oral calcium folinate
regimen provided therapeutic benefit, accompanied by a good
quality-of-life profile. This study continues to recruit patients.
The final analysis will determine whether these results are borne out
among a larger body of patients over a longer period of observation.
1. Feliu J, Gonzalez Baron M, Zamora P, et al: Experience of Oncopaz
Cooperative Group with oral fluoropyrimidines in tumors of the
stomach, lung, head and neck, and breast. Oncology 54(suppl 1):30-37, 1997.
2. Monserrat D, Diaz-Rubio E, Guillem V, et al: Phase II trial of UFT
activity in pretreated breast cancer patients. Jpn J Clin Oncol
3. Pazdur R, Lassere Y, Rhodes V, et al: Phase II trials of uracil
and tegafur plus oral leucovorin: An effective oral regimen in the
treatment of metastatic colorectal carcinoma. J Clin Oncol
4. Villalon A, De Guzman L, Samson M, et al: A comparative,
randomized trial of UFT and 5-fluorouracil in combination with
cyclophosphamide and doxorubicin in the treatment of advanced breast
cancer patients at the Philippines General Hospital. Oncology
54(suppl 1):2-6, 1997.
5. Taguchi T: Clinical application of biochemical modulation in
cancer chemotherapy: Biochemical modulation for 5-FU. Oncology
54(suppl 1):12-18, 1997.
6. Ansfield FJ, Ramirez G, Mackman S, et al: A 10-year study of
5-fluorouracil in disseminated breast cancer with clinical results
and survival times. Cancer Res 29:1062-1066, 1969.
7. Haskell CM, Giulano AE, Thompson RW, et al: Breast cancer, in
Haskell CM (ed): Cancer Treatment, 2nd ed, pp 137-180. Philadelphia,
WB Saunders, 1985.
8. Itoh S, Kowishi Y, Harauchi D, et al: Clinical trial of UFT
against disseminated breast cancer. Gan To Kagaku Ryoho 11:2381-2385, 1984.