|
Original Article
A pilot study evaluating the safety and toxicity of epirubicin,
cisplatin, and UFT (ECU regimen) in advanced gastric
carcinoma
1Departments of Medical Oncology, Istanbul University Oncology Institue; 2Pathology, Istanbul Medical Faculty, Istanbul University; 33Department of General Surgery, Istanbul Medical Faculty, Istanbul University, 4Department of General Surgery, Istanbul University Oncology Institue, Istanbul, Turkey
|
|
Abstract
Background: Best response rates have been achieved with three-drug regimens containing 5-FU in the treatment of advanced gastric cancer (AGC) and oral fluoropyrimidines are the best alternatives as substitutes for infusional 5-FU. This study aimed to evaluate the safety and toxicity of epirubicin, cisplatin, and UFT (ECU regimen) regimens in AGC outpatients.
Materials and methods: Forty-one patients with AGC received epirubicin, cisplatin, and oral UFT plus leucovorin. Epirubicin 50 mg/m² and cisplatin 60mg/m² were administered on Day 1. Three hundreds (300) mg/m²/day UFT was administered with leucovorin at a fixed oral dose of 90 mg/day for 21 days, followed by a 7-day rest period. Cycles were repeated every 4 weeks. Performance status was either as 0 and 1.
Results: Among the 41 patients enrolled, complete and partial response was achieved in 7.3% and 36.6% of patients, respectively, with an overall response rate of 43.9%. Stable disease was observed in 34.1% of patients and 22% showed disease progression. Median time to progression was 5.2 months and median survival was 12.3 months. A median of 4 cycles (range: 1-6) of chemotherapy were administered. The main grade III-IV toxicities were nausea/vomiting (19.4%) and neutropenia (12.1%). Grade IV toxicities were gastric perforation and renal failure.
Conclusion: ECU appears to be an effective regimen in the treatment of AGC, with acceptable tolerability and manageable toxicity. In three-drug regimens, substitution of infusional 5-FU by UFT offers the possibility of increased AGC outpatient compliance.
Key words
advanced gastric carcinoma, cisplatin, epirubicin, UFT
J Gastrointest Oncol 2011; 2: 19-26. DOI: 10.3978/j.issn.2078-6891.2010.030
|
|
Introduction
Gastric cancer is one of the most challenging diseases
among all cancer types. It is the fourth most common
cancer worldwide, with an estimated 934 000 new cases per
year in 2002 (9% of new cases globally), and occurs nearly twice as often in men (1). In the United States, mortality due
to gastric cancer has declined and five-year relative survival
rates improved from 16% to 24% between 1975 and 2002
(2). In Turkey, gastric cancer is the second leading cause of
death in men and the third leading cause of cancer mortality
in women (3). The anatomical site of origin of gastric
cancer among Turkish patients differs from that reported
for Western countries, with 48.1% and 41.2% of cancers
in Turkish patients occurring at the antrum and corpus,
respectively, and 51.6% of patients having a pathological
grade III cancer (4).
Surgery is the main treatment modality for gastric cancer.
Only in Japan, the majority of patients are surgically treated
at stage I (5). The reported median survival benefit in AGC
patients receiving chemotherapy is approximately 6 months (6), and the reported benefits of novel chemotherapy
regimens for AGC have been shown to not exceed 12
months in recent Phase III trials in Western countries (7,8).
Fluorouracil- (5-FU) based chemotherapies are the
mainstay of treatment for AGC. Since continuous 5-FU
infusion has shown promising results in the treatment
of AGC in Phase II trials, combination therapies have
been developed (9). Oral f luoropyrimidines are the best
alternative to infusional 5-FU in three-drug regimens
for AGC. Tegafur (UFT) is an oral f luoropyrimidine
and its antitumor activity is known to generate plasma
5-FU levels that are similar to those of infusional 5-FU
(10-12).
This pilot study was conducted to examine the safety
and toxicity of combination chemotherapy consisting of
epirubicin, cisplatin, and UFT regimen in chemo-naïve
AGC outpatients.
|
|
Patients and methods
Patients
Forty-one AGC patients who admitted to Istanbul
University Oncology Institute between September 2003
and December 2006 were included in this study. Patients
with histologically or surgically proven metastatic or locally
advanced inoperable gastric carcinoma were eligible. They
were required to have a performance status (PS) level of (0)
or (1) according to WHO criteria. There was no age limit.
Informed consent was obtained from all patients and the
study was approved by the Institutional Review Board. All
patients were required to have a leukocyte count ≥ 4000/
μL; platelet count ≥ 100 000/μL; hemoglobin ≥ 10.0 g/dL;
aspartate transaminase (AST) and aminotransferase (ALT)
below two times the upper normal limit; creatinine serum
level ≤ 1.3 mg/dL; and total serum bilirubin
Drug administration and dose adjustments
The following regimen was given to patients: cisplatin (60
mg/m²) IV 1-hour infusion with standard hydration on Day
1; epirubicin (50mg/m²) IV 30 minutes infusion on day 1;
UFT (Tegafur/uracil; Bristol Myers Squibb, Spain) 300
mg/m² taken orally on days 1-21 (q 28-d); and leucovorin
(Rescuvolin®, Netherlands) administered 90 mg/day orally
on days 1-21 (q 28-d).
The total daily dose of UFT was divided into three
doses given every 8 hours, beginning with an initial dose of 300 mg/m2/day. UFT was supplied in the form of 100 mg
capsules (100 mg tegafur and 225 mg uracil). Leucovorin
was supplied as 15 mg oral tablets and the fixed total daily
dose (90 mg) was divided into three doses. Treatment was
repeated every 4 weeks until disease progression, patient
refusal, intolerance to therapy, or unacceptable adverse
reactions occurred.
ECU regimen dose reduction was planned in the event
of severe hematological and/or non-hematological toxic
events. Hematological tests were performed at baseline
in all patients and they were repeated in asymptomatic
patients before the beginning of each cycle. In patients
with signs and symptoms of hematological toxicity, the
tests were ordered at the onset of the symptoms and
weekly thereafter until the condition resolved. The doses
of UFT, epirubicin, and cisplatin were reduced 25% in
subsequent cycles in the event of the following conditions:
1) Grade III-IV neutropenia or thrombocytopenia lasting
for seven days or more, and 2) Grade IV non-hematological
toxicity. In cases of insufficient hematological function
(neutrophil count <1500/μL and platelet count <100 000/
μL) chemotherapy was delayed for as long as 14 days.
If no recovery occurred at this point, treatment was
discontinued. A maximum of 2 dose reductions were
allowed per patient. Cisplatin doses were reduced 25%
when the creatinine level was between 1.4 and 1.9 mg/dl.
For a creatinine level between 2.0 and 2.2 mg/dl, a 50%
dose reduction was allowed.
Study end points and evaluation of treatment
This was a single-center pilot study. The primary objective
was to evaluate the safety and toxicity of the ECU regimen
in AGC outpatients. The secondary objectives were to
determine time to progression (TTP), overall survival
(OS) rates, and response rates. Toxicity was graded and
defined using NCI CTC Version 2. RECIST criteria were
used to assess response to treatment. For the evaluation
of response, the extent of measurable disease was assessed
by computerized tomography before the first cycle and
after every 2 cycles. Time to progression was defined as
the duration from the initiation of the regimen to the date
of documented disease progression or death by any cause.
Overall survival was defined as the duration from initiation
of chemotherapy to the date of death or last follow-up.
Statistical analysis
Kaplan-Meier analysis was used for TTP and overall survival
analyses and the log-rank test was used for comparisons.
Survivors were censored on the date they were last known
to be alive.
|
|
Results
Patient characteristics
Patient characteristics are shown in Table 1. No patient
was withdrawn from the study. Al l patients had PS0 or PS1. Two patients (4.9%) had gastroesophageal
adenocarcinomas, 15 (36.6 %) had corpus tumors, and 17
(41.5%) had antral tumors. Twenty-two patients (53.7%)
had histopathologically grade III tumors and 19 (46.3%)
had grade II tumors. Eight patients (19.5%) had locally
advanced tumors and the remaining had metastatic disease.
Median age of patients was 54 (range: 26-71).
Response to chemotherapy
One-hundred fifty-nine courses of treatment were
administered. The median delivered dose intensities of
epirubicin, cisplatin, and oral UFT were 91.8%, 92.5%, and
91.2%, respectively. The median number of chemotherapy
cycles was 4 (range: 1-6) and average duration of follow-up
was 12.7 months (range: 2.9-49.5) (Table 2).
Three patients (7.3%) had complete response after 6
(n=2) or 4 cycles (n=1). Fifteen patients (36.6%) had partial
response and 14 (34.1%) had stable disease. Nine patients
(22%) showed progression. The overall response rate was
43.9% (complete response plus partial response) (95% CI;
28.5-60.3) (Table 2).
Twelve patients (29.2%) required dose modification
only once during treatment and 2 patients (4.9%) required
dose modification twice. Of the 2 patients with locally
advanced disease who underwent surgery after 6 cycles
of chemotherapy, 1 is still alive and the other died due to
postoperative complications. Brain metastasis developed in
one patient after 3 cycles of chemotherapy.
Toxicity
The main grade III-IV non-hematological toxicities
encountered with the ECU regimen were nausea and
vomiting (19.5%). Neutropenia was the main grade IIIIV
hematological toxicity (12.1%; Table 3). Grade III-IV
diarrhea occurred in 4 patients (9.8%). Reasons for dose
modifications were prolonged neutropenia, neutropenic
fever, hypopotassemia, diarrhea, and anorexia.
The most serious grade IV adverse events included acute
renal failure (2.4%) and gastric perforation (2.4%). A gastric
perforation that occurred after 1 cycle of chemotherapy
in a patient with locally advanced disease was repaired
surgically and the patient continued treatment with 4 cycles
of cisplatin and infusional 5-FU and survived for 23 months.
Acute renal failure developed in 1 female patient due to
grade IV diarrhea, nausea, and vomiting after the fifth cycle.
She did not seek medical help immediately, resulting in a delayed admission to hospital. She was subsequently treated
with hemodialysis and recovered.
Grade III hypokalemia occurred in 1 patient (2.4%)
without diarrhea, nausea, or vomiting. Deep vein and portal
vein thrombosis developed in 2 other patients (4.9%) who
were considered to have disease progression. There were
no chemotherapy-related deaths. Eight patients (19.5%)
discontinued chemotherapy due to intolerance after 1 to 5
cycles. Toxicity-related treatment delays were observed in
17 patients (41.5%).
Survival
Median time to progression was 5.2 months (95% CI:
0.53 -9.86) and median overall survival was 12.3 months
(95% CI: 5.3-19.3) (Fig 1). One year survival was 68.4%
for patients with grade II tumors (16.3 months; 95%CI:
10.6-21.9) and 27.3% for those with grade III tumors (7.3
months; 95% CI: 5.62-8.41), corresponding to a significant
difference in survival rate (P=0.05) (Fig 2).
   
Figure 1 Kaplan-Meier curve for the cumulative survival
probability of all patients
Figure 2 Kaplan-Meier curves showing the significant
survival difference between grade II and grade III tumors
|
|
Discussion
Management of AGC has been evolving since the 1990’
s. Pyrhonen showed the advantage of chemotherapy
compared to best supportive care (BSC) in AGC in a small
sample size using bolus 5-FU (13). Findlay showed that
the administration of epirubicin, cisplatin, and continuous
infusion 5-FU (ECF) was associated with an objective
tumor response rate of 71% (14). These encouraging results led to a randomized trial in which ECF was compared
with FAMTX (fluorouracil-doxorubicin-methotrexate)
(15). In that study, median survival of patients receiving
ECF (8.9 months) was also better, compared to FAMTX
(5.7 months). As a result, the benefits of infusional 5-FU
in the treatment of AGC was definitively established for
the first time in terms of clinical response and overall
survival. Folates are known to prolong the retention of the
5-f luoro-2’-deoxyuridine 5’-monophosphate (FdUMP)-
TS complex (16). Inhibition of TS by FdUMP is thought
to be the primary mechanism for the action of 5-FU (17).
A two-drug regimen consisting of cisplatin and 5-FU was
shown to decrease TS mRNA levels in adenocarcinoma
of the stomach, which explains the mechanism of action
of combination therapies (18). Subsequent meta-analyses
showed best results with three-drug regimens in AGC
patients (6).
UFT is a combination (in a 1:4 M ratio) of tegafur, an oral
prodrug of 5-FU that is metabolized to 5-FU primarily in
the liver, and uracil, a natural substrate for the liver enzyme
dihydropyrimidine dehydrogenase (DPD). Compound
uracil serves as a competitive antagonist for DPD and
enhances the concentration and half-life of 5-FU (11,12).
UFT is administered alone or with folinic acid (leucovorin)
tablets to increase the effect on thymidylate synthetase
(TS).
Oral UFT monotherapy with leucovorin has shown
overall response rates (ORRs) of 10.5-28% and median
OS rates of 5.8-6.1 months (19,20), which is similar to those reported for 5-FU single-agent continuous infusion
(11). ORRs with two-drug regimens (UFT and cisplatin,
etoposide, or paclitaxel) were 35%-51% and average OS was
8.1-10.1 months in the treatment of AGC patients (21-23).
Finally, three-drug regimens with oral UFT have shown
promising results in the treatment of AGC (24-28). Even
complete remission of AGC has been reported using the
suppository form of UFT (29). UFT is absorbed readily in
the gastrointestinal system, which helps improve patient
compliance and maintain constant plasma levels of 5-FU. In
addition, catheter-related complications are avoided (30).
Although UFT and leucovorin doses have been studied
for the last two decades, to date, an optimal administration
schedule has not been established. The goal of adding
leucovorin is to increase efficacy without additional toxicity.
Newman (31) and Buroker et al. (32) showed no survival
advantage of high-dose leucovorin but observed increased
toxicity. On the other hand, in a randomized study of colon
cancer patients, Köhne et al. found a benefit only in terms of
better progression-free survival when leucovorin was added
to 5-FU (33). However, this benefit was at the expense of
increased toxicity. Pazdur et al. showed that UFT with
leucovorin was equal to FUFA in colon cancer treatment,
with less toxicity in favor of UFT (34). No studies have
ever compared UFT versus UFT/LV treatment in gastric
and colon cancers, but colon cancer studies usually provide
guidance for approximate UFT doses. Fixed leucovorin
doses between 25 mg/m² and 90 mg/m2 have been given to
patients, but it is primarily the UFT dose that accounts for
the overall response rate and toxicity (22,27-30). Therefore, low doses of leucovorin might be recommended as opposed
to not implementing UFT at all.
In this study, administration of the ECU regimen in
AGC patients was associated with acceptable toxicity. The
most serious toxicities observed were gastric perforation
and acute renal failure. The patient with gastric perforation
had locally advanced linitis plastica and lived for 23 months.
This is a very rare complication, with only one case reported
in the after a single cycle of UFT (35). Perforation may be
attributed to impaired connective tissue repair induced
by chemotherapy in the tumors (36) and/or it may be the
result of chemosensivity. The other serious toxicity event
was acute renal failure, which was directly related to delayed
hospitalization for grade IV diarrhea, vomiting, and nausea.
Previously, Woo reported a patient with grade IV diarrhea,
vomiting, and nausea who required a 75% reduction in
cisplatin dose (29), and Kim reported one case with grade
IV diarrhea that received the same three-drug UFT regimen
and required hospitalization (27).
In this study, grade III-IV mucositis was not observed,
but grade III-IV diarrhea occurred in 4 patients (9.8%). If
UFT doses as high as 480 mg/m2 had been used as a single
agent, more cases with grade III-IV mucositis and diarrhea
might have been observed (29). In a study by Kim et al.,
grade III-IV mucositis was reported in 13% of patients
receiving a UFT dose of 360 mg/m², while other studies
reported mucositis in 6% of subjects receiving 300 mg/m²
UFT in ECU regimens. The incidence of diarrhea was also
higher in the former study (10.8% vs 24-27).
The incidence of grade III-IV neutropenia (11.9%) was lower in this study compared to other studies with
epirubicin, cisplatin, and UFT regimens (24-27,29).
A 1-week drug-free interval after 3 weeks of UFT
administration, the exclusion of patients with PS 2, and
no UFT doses above 300 mg/m2 may account for this low
incidence (Table 4). Hand-foot syndrome, neurotoxicity,
or cardiac problems were not observed in this study,
which may be attributed to the uracil component of UFT,
since it is known to prevent skin exfoliation and cardiac
events (37-40). Thrombosis occurred in 2 patients (4.9%).
Thrombosis is an important toxicity event during the
treatment of AGC; it occurs frequently at the initiation and
during the course of chemotherapy, resulting in poor OS
(41).
In addition to its acceptable toxicity profile and
convenience of administration on an outpatient basis,
the ECU regimen also appears to be promising in terms
of efficacy. Overall median survival was 12.3 months
compared to 8.2 months obtained in a previous study
with the ECF regimen (epirubicin, cisplatin, infusional
5-f luorouracil) (14). Conversely, overall response rates
varied between 25% and 71% in studies using the ECF
regimen for AGC (14,42), whereas they varied between 38%
and 54% in studies with the ECU regimen (including this
study) (24,25). Therefore, the efficacy of ECU versus ECF
needs to be studied in larger controlled trials.
One-year survival rates for Grade II and Grade III
tumors were 68.4% and 27.3%, respectively (P=0.05). The
proportion of patients with grade III tumors in this study
is close to the general profile of Turkish patients with
AGC (4). In future studies, the efficacy and safety of the
ECU regimen should be studied in patients with different
pathological grades. Another important factor affecting
treatment outcome is the performance status of patients
with AGC. It has a direct impact on survival, as shown in
a meta-analysis by Yoshida in AGC (43) . The relationship
between performance status and survival can be seen in
Table 4.
 |
|
Conclusion
This study has shown the feasibility of the ECU
chemotherapy regimen, with manageable toxicity in an
outpatient setting for patients with AGC. UFT could be
considered as a substitute for infusional 5-FU and the ECU
regimen might represent a treatment model for three-drug
regimens for the management of AGC.
|
|
References
Cite this article as:
Saglam S, Aykan N, Sakar B, Gulluoglu M, Balik E, Karanlik H. A pilot study evaluating the safety and toxicity of epirubicin,
cisplatin, and UFT (ECU regimen) in advanced gastric
carcinoma. J Gastrointest Oncol. 2011;2(1):19-26. DOI:10.3978/j.issn.2078-6891.2010.030
|
