Adenocarcinoma of the stomach is one of the
leading causes of cancer-related death in Japan, Eastern Europe, and
South America. There has been, however, a significant decrease in
incidence in the United States and Western Europe.[1,2] The prognosis
for patients remains extremely poor with 5-year survival rates
ranging from 5% to 15%.
Despite surgical efforts, gastric carcinoma resection as a
curative approach yields dismal results, and at least 80%
of patients develop recurrent and metastatic disease. Single drugs
with reported response rates between 20% and 36% are 5-fluorouracil
(5-FU),[3,4] mitomycin C (Mutamycin), doxorubicin (Adriamycin),
and cisplatin (Platinol).[6,7] Complete responses, however, are
uncommon and in general, responses are of brief duration without a
significant impact on survival.
In order to improve response rates and increase survival, combination
regimens have been developed, including FAM (5-FU, Adriamycin,
mitomycin C),[4,8] FAP (5-FU, Adriamycin, Platinol), PFU
(Platinol, 5-FU), EAP (etoposide [VePesid], Adriamycin,
Platinol),[11-14] ELF (etoposide, leucovorin [Leucovorin Calcium,
Wellcovorin], 5-FU), FAMTX (5-FU, Adriamycin, methotrexate
[Folex, Mexate]),[16,17] and ECF (5-FU, epirubicin, cisplatin).
In initial phase II studies, response rates with these combinations
have reached 40% to 60% and complete responses of 2% to 15% have been
reported. However, there has been no improvement in median duration
of survival (which remained at 6 to 10 months).
At present, only protocols with FAM or FAM associated with BCNU have
been compared to single-drug 5-FU chemotherapy. These studies failed
to demonstrate a significant increase in response[19,20] or survival
rates.[4,19,20] Phase III trials conducted to compare
polychemotherapy regimens have also not shown a reproducible
significant advantage over any other regimen.[14,17,18] Moreover,
some of these protocols were associated with a significant increase
in toxicity. The EAP, and to a lesser extent FAMTX, regimens induced
severe toxicity (consisting mainly of myelotoxicity).[11-14,16-18]
Uracil and tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil) in a molar
ratio of 4:1 comprise the compound UFT. Tegafur is converted to 5-FU
in vivo. The coadministration of uracil in the form of UFT/oral
calcium folinate has been shown to enhance the concentration of 5-FU
in tumors and the resulting antitumor activity of tegafur. In
vivo studies showed that UFT/oral calcium folinate resulted in 5 to
10 times greater accumulation of 5-FU in tumors than in normal
tissue. UFT/oral calcium folinate is the first member of the second
generation of 5-FU prodrugs that has been previously evaluated for
metastatic gastric carcinoma in Japan.[22,23] Recently, this agent
became available for clinical trials in Europe and North America
based on promising initial results indicating a single-agent overall
response rate of 27.7%.[22,23]
Eligible adult patients had histologically proven gastric cancer with
measurable distant metastatic disease, an Eastern Cooperative
Oncology Group (ECOG) performance status £
2, and a life expectancy > 3 months. They could not have received
chemotherapy or radiotherapy for 4 weeks prior to study entry.
Adequate organ function was required. Patients had to give written
informed consent before entering the trial.
A clinical history and physical examination was recorded for each
patient. Preinclusion staging included abdominal computed tomographic
scans and scans from other fields depending on the site of the
metastatic disease. Laboratory parameters such as a complete blood
count and differential, electrolytes, and renal and liver function
tests were determined. All patients had a baseline electrocardiogram.
UFT was administered orally at a dose of 300 mg/mg² daily for 28
consecutive days. The total daily dose was divided and administered
every 8 hours (each dose equaled about 100 mg) with calcium folinate
given concurrently at 90 mg daily for 28 days. A 7-day rest followed
and the next cycle was scheduled to begin on day 36.
Intracycle or intercycle dose modification was allowed depending on
toxicities as graded by the Common Toxicity Criteria (CTC).
If a CTC grade 3 toxicity for granulocytes or platelets was noted
during any cycle of treatment, UFT/calcium folinate administration
was suspended until granulocytes rose to ³
1.5 × 109/L and the platelet count reached ³
100 ×109/L. Following recovery, the UFT dose was
reduced by 50 mg/m²/d. Where there was nonhematologic toxicity
CTC grade ³ 2, with the exception of
untreated anemia, inadequately treated nausea or vomiting, alopecia,
and asthenia, UFT/oral calcium folinate therapy was discontinued
until the toxic event completely resolved or returned to baseline.
Therapy was resumed at the same dose level if toxicity was CTC grade £
2. For CTC grade 3 or 4 toxicities, therapy was resumed at a UFT dose
reduced by 50 mg/m²/d or 100 mg/m²/d, respectively. The
days therapy was withheld because of toxicity were counted as
treatment days. UFT/oral calcium folinate therapy was discontinued on
day 28 of each cycle, regardless of any interruptions.
Before the start of the next cycle of treatment, dose adjustments
were made based on the maximal toxicity observed during the previous
cycle of treatment. The initiation of a new cycle of treatment was
delayed until recovery of neutrophil count to ³
1.5 × 109/L and platelet count to ³
100 × 109/L. Nonhematologic toxicities had to return
to baseline or CTC grade 1.
Evaluation of Treatment
Response was assessed every 10 weeks. The work-up was identical to
the initial pretreatment evaluation.
From July 1997 to December 1997, 38 patients with metastatic gastric
carcinoma were entered into the trial. All patients but two, who died
before starting treatment because of progressive disease, were
assessable for toxicity. Twelve patients were considered unassessable
for tumor response: two died before receiving treatment and no final
information was available from 10 patients. Median age of
participants was 64 years (range, 43 to 76). Most patients had an
ambulatory performance status: 13 patients (34.2%) had an ECOG
performance status of 0, 20 (52.6%) had a status of 1, and five
(13.2%) had a performance status of 2.
Administration of Treatment
Thirty-six patients received a total of 94 courses of treatment.
Seventy-eight courses were administered at the planned UFT dose. In
16 courses (17%), the dose had to be decreased to 250 mg/m²/d.
Toxicities encountered were evaluated according to the CTC grading
system. The main toxicities were diarrhea (21 patients), nausea and
vomiting (20), asthenia, malaise (8), and stomatitis (6). Thirty-two
grade 3 and 4 events (34%) were reported among 94 courses of
treatment. They were predominantly diarrhea (grade 3, seven; grade 4,
two), nausea (grade 3, four), vomiting (grade 4, three), asthenia
(grade 3, one; grade 4, two) and neutropenia (grade 3, four; grade 4,
one). Six patients had to discontinue because of excessive toxicity.
Response to Treatment and Survival
At the time of analysis, of 26 evaluable patients one achieved a
complete response and three achieved partial responses. Six patients
had stable disease.
Our preliminary data indicate that UFT/oral calcium folinate provides
moderate activity in patients with metastatic gastric cancer. The
more frequent toxicities were diarrhea, nausea, vomiting, and
asthenia, with the main CTC grade 3 and 4 toxicities being diarrhea,
nausea, and vomiting. The efficacy and limited toxicity seen in this
trial confirm the rationale for continuing UFT/oral calcium folinate
testing in metastatic gastric cancer patients.
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