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Epirubicin, Cisplatin, Oral UFT, and Calcium Folinate in Advanced Gastric Carcinoma

Epirubicin, Cisplatin, Oral UFT, and Calcium Folinate in Advanced Gastric Carcinoma

ABSTRACT: UFT (uracil and tegafur in a 4:1 molar ratio) plus calcium folinate treatment has favorable activity and tolerable toxicity in patients with advanced gastric carcinoma. High response rates have been reported in patients with advanced gastric carcinoma receiving a schedule of epirubicin, cisplatin (Platinol), and protracted infusion of 5-fluorouracil (5-FU). Replacing the inconvenient infusion pump and intravenous catheter needed for protracted infusion of 5-FU, we administered oral UFT plus calcium folinate (Orzel) to 37 patients (median age, 55 years; median World Health Organization [WHO] performance status of 1) with locally advanced or metastatic gastric carcinoma. Epirubicin 50 mg/m² and cisplatin 60 mg/m² were administered by intravenous injection on day 1; UFT 360 mg/m²/day po was administered in conjunction with oral calcium folinate 25 mg/m²/day in divided daily doses for 21 days, followed by a 7-day rest period. Courses were repeated every 4 weeks. Among 37 evaluable patients who received a median of four courses of treatment (range, 2 to 10), two achieved a complete response and 18 a partial response, for an overall response rate of 54% (95% confidence interval, 39% to 70%). Stable disease was reported in 12 patients (32.4%) and disease progression in another five (13.5%). The median duration of survival was 10 months (range, 2 to 15+). The main toxicities were nausea/vomiting, leukopenia, diarrhea, and oral mucositis. WHO grade 3 or 4 toxicity included leukopenia in 14 patients (37.8%), nausea/vomiting in 11 (29.7%), oral mucositis in five (13.5%), and diarrhea in four (10.8%). Epirubicin, cisplatin, and oral UFT plus calcium folinate, a convenient outpatient regimen, has significant activity and tolerable toxicities in patients with gastric carcinoma. [ONCOLOGY 7(Suppl 3):64-68, 1999]


Although the incidence of gastric carcinoma has
decreased in most Western countries,[1] it is still an important
cause of cancer mortality and its treatment remains a challenge.
Because the majority of patients have metastatic disease either at
presentation or later, the development of systemic chemotherapeutic
treatments is mandatory to improve clinical outcome for patients with
gastric carcinoma. Given the predominantly palliative intent of
advanced gastric carcinoma therapies, regimens with both low toxicity
and acceptable activity should be chosen for patients in this category.[2]

During the past decade, the development of new regimens that may
represent a step forward in the treatment of advanced gastric
carcinoma encouraged the medical community. Until recently, the most
extensively used combination was FAM (5-fluorouracil [5-FU],
Adriamycin [doxorubicin], mitomycin-C [Mutamycin]), which produced
objective response rates of 30% to 35%, median remission of 6 to 9
months, and median survival of 7 months.[3] However, the FAM regimen
failed to improve median survival when compared with single-agent
5-FU.[4] Moreover, in two randomized studies, FAM was found to be
inferior to FAMTX (5-FU, Adriamycin [doxorubicin], methotrexate) and
to PELF (Platinol [cisplatin], epirubicin, leucovorin [calcium
folinate], 5-FU).[5,6]

The ECF (epirubicin, cisplatin, 5-FU) regimen was developed in the
gastrointestinal unit of the Royal Marsden Hospital and first
reported in 1990.[7] The choice of the three drugs in the regimen was
based on their single-agent activity in upper gastrointestinal
cancer[8-11] and the potential synergy between 5-FU and cisplatin
shown in experimental models.[12] An anthracycline was included based
on the anticipated enhanced cytotoxicity afforded by combining it
with the other two drugs. Evidence for this potential increased
efficacy is provided by the results of a randomized trial of advanced
gastric carcinoma, in which the addition of epirubicin to a
combination of bolus 5-FU and cisplatin resulted in a significant
survival benefit compared with that for 5-FU and cisplatin alone.[13]

The regimen was also designed to minimize systemic toxicity; hence,
epirubicin was chosen instead of doxorubicin because of its lower
rates of mucositis and cardiac toxicity.[14] 5-Fluorouracil was
administered by protracted venous infusion because this schedule has
been shown to produce higher response rates and less myelotoxicity
compared with bolus administration for patients with colorectal carcinoma.[15]

A potential drawback of the ECF regimen is the central venous line
and the portable infusion pump; protracted infusion of 5-FU adds to
morbidity and cost.[16] Long-term UFT (uracil and tegafur in a 4:1
molar ratio) offers the advantage of oral administration mimicking
the effects of protracted 5-FU infusion.[17] In our previous report,
an outpatient regimen of oral UFT plus calcium folinate (Orzel)
provided favorable activity in gastric carcinoma patients, with
tolerable toxicities.[18] We therefore designed a phase II trial of
epirubicin, cisplatin, UFT, and calcium folinate, replacing 5-FU with
oral UFT and calcium folinate.

Materials and Methods


Between April 1997 and June 1998, 37 patients seen at the Korea
University Anam and Guro Hospital entered the study. All patients had
locally unresectable or disseminated adenocarcinoma of the stomach
confirmed by biopsy, with measurable or evaluable disease.
Eligibility requirements included age younger than 75 years and a
life expectancy of at least 4 weeks. Required prestudy laboratory
parameters included a white blood cell count > 4.0 × 109/L,
platelets > 100 × 109/L, and bilirubin and
creatinine values of < 2.0 mg/dL. Patients who had received prior
5-FU or other chemotherapeutic agents were eligible for the trial.
All patients provided informed consent.


Epirubicin 50 mg/m² was given as a bolus intravenous injection
every 4 weeks. Cisplatin 60 mg/m² was administered as a 4-hour
intravenous infusion every 4 weeks with standard hydration. If on the
day of treatment the white blood cell count was < 2.0 × 109/L
or platelets were < 100 × 109/L, epirubicin and
cisplatin were delayed for 1 week or until myelosuppression had
resolved. A second treatment delay due to myelosuppression or an
episode of World Health Organization (WHO) grade 4 myelosuppression
required a 25% dose reduction of epirubicin and cisplatin on
subsequent treatments. If there were repeated episodes of grade 3 or
4 myelosuppression, in spite of dose modification, treatment was stopped.

Oral UFT and calcium folinate were administered for 21 consecutive
days, followed by a 7-day treatment-free interval. The total daily
UFT dose was divided into three doses administered orally every 8
hours, beginning with an initial dosage of 360 mg/m²/day. UFT
was supplied in the form of 100-mg capsules (100 mg of tegafur plus
225 mg of uracil). Calcium folinate was supplied as 5-mg tablets and
administered orally, with the total daily dose divided into four
doses. If a patient had a body surface area of 1.7 m², the total
daily calcium folinate dose was 40 mg (eight tablets). In subsequent
courses, the daily dose of UFT was increased by 100 mg/day if
toxicity was absent or mild at the 360-mg/m² dose level. The
calcium folinate dosage, however, remained at 25 mg/m²/day. On
the next course, the daily dose of UFT was reduced by 100 mg/day in
patients with grade 3 or 4 nonhematologic toxicity, based on WHO
criteria. Oral administration of UFT and calcium folinate was
interrupted if the patient developed grade 3 or 4 nonhematologic
toxicity that did not resolve with UFT dose reduction. Treatment was
reinstituted after clinical symptoms resolved. Courses were repeated
every 4 weeks until tumor progression or the development of treatment intolerance.


All patients were examined clinically prior to entry into the study.
Baseline investigations included a complete blood cell count and
estimation of serum electrolytes, urea, creatinine, calcium,
phosphate, bilirubin, alkaline phosphatase, aspartate
aminotransferase, total proteins and albumin, carcinoembryonic
antigen, and a-fetoprotein. Upper
gastrointestinal endoscopy, double-contrast upper gastrointestinal
radiographs, abdominal computed tomography, and other appropriate
procedures were also performed. Patients were evaluated weekly using
routine blood tests at the outpatient clinic. Unless disease
progressed unequivocally or the patient had dropped out of the study
because of drug toxicity, disease status was reevaluated
radiologically every two cycles. Standard WHO response criteria were
used to assess response to treatment.[19] Toxicity was also reported
using WHO criteria. Response duration was calculated from the date
that the response was confirmed to the date that progressive disease
was first observed. Survival duration was calculated from the first
day of treatment to death or the last follow-up.


Patient Characteristics

A total of 37 consecutive patients were entered in this trial.
Patient characteristics are listed in Table
. Of these patients, 23 (62%) had WHO performance status grade
0 or 1; seven patients were evaluated as grade 3. The median patient
age was 55 years, with a range of 34 to 74 years. Four patients had
been treated previously with 5-FU–containing chemotherapy (two
had received paclitaxel [Taxol], 5-FU, cisplatin [Platinol]; the
other two had received postoperative adjuvant 5-FU, cytosine
arabinoside, cisplatin). Of the 37 patients, 32 had metastatic
disease at the start of treatment and five had locally advanced
unresectable disease.

Response to Chemotherapy

The 37 enrolled patients received 171 courses of treatment; the
median number of courses per patient was four, with a range of two to
12 (Table 2). Overall, at least
95% or more of all drugs were administered per cycle (epirubicin and
cisplatin, 97.5%; UFT, 95%), with 16 patients (43%) requiring dose
modification during treatment.

With 20 of 37 evaluable patients responding, the overall objective
response rate was 54% (95% confidence interval, 39% to 70%),
including two (5.4%) complete remissions. Of 27 patients with
measurable disease, 17 (63%) responded to treatment, and of 10
patients with evaluable disease, another three (30%) responded. Two
patients who had relapsed lung metastasis after curative surgical
resection achieved complete remissions, with response durations of
11+ and 8+ months. One patient who had failed to respond to a regimen
of paclitaxel, 5-FU, cisplatin achieved a partial response and had
disease progression after 3 months. Other patients who had received
previous chemotherapy did not respond to this therapy. One complete
responder had been treated with six cycles of 5-FU, cytosine
arabinoside, cisplatin chemotherapy as adjuvant therapy 3 years
before the disease relapse.

Responses were frequently observed in the patients with metastases of
liver (7/13, 53.8%) or lymph nodes (6/10, 60%), or in the patients
with localized unresectable disease (3/5, 60%). However, patients
with peritoneal disease did not respond, and three patients had
stable disease as their best response during therapy. After a median
follow-up of 8 months, the median survival time was 10 months (range,
2 to 15+ months) for 37 patients (Table


The main toxicities encountered with epirubicin, cisplatin, oral UFT,
and calcium folinate were leukopenia and nausea/vomiting (Table
). WHO grades 3 and 4 leukopenia were observed in seven and
seven patients, respectively. Six patients with grade 4 leukopenia
required dose modification on subsequent courses. Treatment was
discontinued in one patient because of prolonged myelosuppression
after treatment with a reduced dosage of epirubicin and cisplatin.
Grades 2 and 3 nausea/vomiting were observed in 43.3% and 29.7% of
the patients, respectively. Significant nausea continued to affect 11
patients for more than 2 weeks and only resolved on cessation of UFT
administration. The dosage of UFT was reduced in the subsequent
course of treatment for those patients. Four patients experienced
grade 3 diarrhea severe enough to require temporary cessation of
treatment, and three of these patients were hospitalized. Grade 3 or
greater stomatitis occurred in five patients. Alopecia was detected
in all patients. No severe infection or treatment-related death occurred.


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