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1
Continuous Infusion of 5-Fluorouracil and Low Dose
Cisplatin Infusion for the Treatment of Advanced and
Recurrent Gastric Adenocarcinoma
Yong-Suk Chung, M.D.1
Yoshito Yamashita, M.D.1
Tohru Inoue, M.D.1
Tasuku Matsuoka, M.D.1
Bunzo Nakata, M.D.1
Naoyoshi Onoda, M.D.1
Kiyoshi Maeda, M.D.1
Tetsuji Sawada, M.D.1
Yasuyuki Kato, M.D.1
Tetsuhiko Shirasaka, Ph.D.2
Michio Sowa, M.D.1
BACKGROUND. Several chemotherapy studies have suggested that continuous infusion of 5-fluorouracil (5-FU) is more effective than bolus 5-FU. In addition, 5-FU
and cis-Diamminedichloroplatinum-II (cisplatin) in combination have been shown
1
First Department of Surgery, Osaka City University Medical School, Osaka, Japan.
2
Institute for Pathogenic Biochemistry in Medicine, Taiho Pharmaceutical Company, Tokyo,
Japan.
to have synergistic cytotoxicity against several human neoplasms. In this study,
the authors evaluated the efficacy and toxicity of continuous infusion of 5-FU and
low dose cisplatin infusion (FP therapy) in the treatment of advanced and recurrent
gastric adenocarcinoma. The relationship between the response to FP therapy and
several factors was also examined.
METHODS. A total of 26 patients fulfilling standard eligibility criteria were enrolled
in the trial. FP therapy consisted of 5-FU (350 mg/m2/day every day by continuous
infusion) and cisplatin (7.5 mg/m2/day in 100 mL of normal saline infused over 1
hour on Days 1?5 every week) for 4 weeks.
RESULTS. A complete response was observed in 2 cases and a partial response in
11 cases, for an overall response rate of 50%. Patients with good performance
status (PS) (0?1) and differentiated histologic type showed higher response rates
(50.0% and 63.6%, respectively) than patients with poor PS (2 or 3) and undifferentiated histologic type (28.6% and 35.3%, respectively), although there were no significant differences. Patients with low serum levels of immunosuppressive acidic
protein (IAP) showed a significantly higher response rate (71.4%) than those with
high IAP levels (0%). Toxic effects included leukopenia, thrombocytopenia, nausea,
and vomiting; these were not life-threatening and did not require treatment interruption.
CONCLUSIONS. FP therapy is a promising regimen for patients with advanced and
recurrent gastric adenocarcinoma. Serum levels of IAP may predict chemosensitivity. Cancer 1997;80:1?7. q 1997 American Cancer Society.
KEYWORDS: recurrent gastric adenocarcinoma, advanced gastric adenocarcinoma,
5-fluorouracil, cisplatin, biochemical modulation, chemotherapy.
T
Address for reprints: Yong-Suk Chung, M.D.,
First Department of Surgery, Osaka City University Medical School, 1-5-7 Asahimachi Abenoku, Osaka, 545, Japan.
Received December 4, 1996; revision received
March 3, 1997; accepted March 3, 1997.
he incidence of mortality from gastric adenocarcinoma has decreased in recent decades. One reason for improved survival is
early detection of gastric adenocarcinoma by mass screening with
upper gastrointestinal radiography and endoscopy. However, the
prognosis for advanced stages of this disease remains poor. For patients with advanced disease, surgery alone has not been effective
because of a low rate of curative resection and a high incidence of
distant metastasis. Several chemotherapies have been used as adjuvant treatment after surgery or as the principal treatment in patients
with recurrent and inoperable disease.
5-Fluorouracil (5-FU) has been commonly used to treat gastric
adenocarcinoma. A single bolus of 5-FU resulted in a response rate
q 1997 American Cancer Society
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W: Cancer
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CANCER July 1, 1997 / Volume 80 / Number 1
of 21%.1 Recently, 5-FU and cisplatin in combination
have been shown to possess synergistic cytotoxicity
against human neoplasms.2,3. It is thought that cisplatin enhances the antitumor effect of 5-FU by increasing the availability of the reduced folate necessary for tight binding of fluorodeoxyuridylate, a 5-FU
metabolite, to deoxythymidylic acid synthase.4,5 Other
studies have shown that 5-FU is more effective when
administered by continuous infusion instead of by bolus injection.6 ? 9 In this study, we evaluated the efficacy
and toxicities of the combination of continuous 5-FU
infusion and low dose cisplatin infusion (FP therapy)
in the treatment of advanced and recurrent gastric
adenocarcinoma.
PATIENTS AND METHODS
Eligibility Criteria
Patients were required to have histologically confirmed adenocarcinoma of the stomach. To be eligible
for the study, all patients were required to meet the
following entry criteria: age � years; Eastern Cooperative Oncology Group performance status (PS)10 �
measurable or evaluable disease; no chemotherapy or
radiotherapy within 4 weeks prior to entry; no major
concomitant infective, cardiovascular, neurologic, or
respiratory disease; adequate bone marrow function
(defined as leukocyte count �00 cells/mm3 and
platelet count � 100,000 cells/mm3); normal liver
function (defined as a total bilirubin � 1.5 mg/dL,
serum asparate transaminase � 3 times the upper
limit of normal, and serum alkaline phosphatase � 3
times the upper limit of normal); and normal renal
function (defined as serum creatinine � 2.0 mg/dL).
Informed consent was obtained from all patients prior
to entry.
Treatment Schedule
Continuous 5-FU and low dose cisplatin combination
therapy consisted of 5-FU (350 mg/m2/day every day
by continuous infusion) and cisplatin (7.5 mg/m2/day
in 100 mL of normal saline infused over 1 hour on
Days 1 ? 5 every week). This treatment was repeated
weekly for 4 consecutive weeks and followed by a 4week rest period (Fig.1). Hydration, to protect against
nephrotoxicity due to cisplatin, was not given to all
patients. In principle, treatment was continued until
life-threatening toxicities were observed.
Assessment of Response
Patients were evaluated for response every 4 weeks
with standard chest X-ray, computed tomography, ultrasonography, or upper gastrointestinal radiography.
Objective response were classified according to World
Health Organization (WHO)criteria.11 A complete re-
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FIGURE 1. The treatment schedule used in this study, for administration
of continuous 5-fluorouracil (5-FU) infusion and low dose cisplatin infusion, is shown.
TABLE 1
Patient Characteristics
Characteristic
No. of patients
Total no. of enrolled patients
Advanced gastric adenocarcinoma
Recurrent gastric adenocarcinoma
Median age
Range
Gender
Male
Female
Performance status
0
1
2
3
Histology
Differentiated
Undifferentiated
Sites of disease
Stomach
Local recurrence
Liver
Lymph nodes
Skin
26
20
6
63
32?75
22
4
12
7
5
2
9
17
19
3
8
16
1
sponse (CR) was defined as the disappearance of all
measurable lesions and no new lesions for at least 4
weeks. A partial response (PR) was defined as a reduction of at least 50% in the sum of the products of
the longest perpendicular diameters of all measurable
lesions and the absence of new lesions for at least 4
weeks. Stable disease (SD) was defined as a reduction
of less than 50% or an increase of less than 25% in the
sum of the products of the perpendicular diameters
of all lesions without any evidence of new lesions for
at least 4 weeks. Progressive disease (PD) was defined
as an increase of greater than 25% in tumor size or
the appearance of new lesions.
WHO criteria for clinical toxicities were used to
evaluate FP therapy.11 A complete hematologic analysis and serum chemistry test were performed every
week during chemotherapy. Immunosuppressive
W: Cancer
5-FU and Cisplatin for Gastric Adenocarcinoma/Chung et al.
3
TABLE 2
Responses to Treatment
Overall
Stomach
Local
Liver
Lymph nodes
Skin
No. of
patients
CR
PR
SD
PD
Response
rate (%)
95% CI
(%)
26
19
3
8
16
1
2
1
1
0
0
0
11
8
0
2
7
1
11
10
1
6
8
0
2
0
1
0
1
0
50.0
47.4
33.3
25.0
43.8
100.0
{19.6
{22.9
{54.4
{30.6
{25.0
{0.0
CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease.
acidic protein (IAP) was also examined. The overall
duration of response was calculated from the start of
treatment to disease progression, and the survival time
was calculated from the start of treatment to death or
last follow-up.
Statistics
The chi-square test was used for statistical analyses.
P values � 0.05 were considered statistically significant.12
tionship between the response to FP therapy and several factors (Table 3). A threshold value of 800 mg/mL
was applied for IAP. Patients with better PS (0 or 1) and
differentiated histologic type showed higher response
rates (57.9% and 77.8%, respectively) than patients
with poor PS (2 or 3) and undifferentiated histologic
type (28.6% and 35.3%, respectively), although there
were no significant differences. Of importance was the
finding that patients with an IAP value below the
threshold showed a higher response rate (66.7%) than
those with an IAP value above the threshold (0%).
RESULTS
Clinical Characteristics
Twenty-six patients were enrolled in this study.
Twenty patients had advanced gastric adenocarcinoma and 6 patients had recurrent gastric adenocarcinoma. Six patients with advanced disease received FP
therapy as neoadjuvant chemotherapy; therefore,
those patients were excluded from the mean duration
of response and median survival time. Patient characteristics are summarized in Table 1. The median age
of the 26 patients was 63 years (range, 32 ? 75 years).
Nineteen patients (73.1%) had a good PS (0 or 1). The
major sites of assessable lesions were the stomach (in
19 of 28 patients, 67.9%), the lymph nodes (in 16 of
28, 57.1%), and the liver (in 8 of 28, 28.6%).
Response to Treatment
Tumor responses to chemotherapy are summarized in
Table 2. CR was observed in 2 cases and PR in 11 cases,
for an overall response rate of 50% (13 of 26 cases).
Response rates according to the sites of disease were
45.5%, 25.0%, 43.8%, and 100% for stomach, liver,
lymph nodes, and skin, respectively. The mean duration of response was 5.1 months. The median survival
time was 7.3 months. One of two CR cases had local
recurrence after total gastrectomy, and another had
obstructive jaundice due to lymph node metastases at
the hepatoduodenal ligament. We examined the rela-
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Toxicities
As shown in Table 4, the toxic effects were hematologic
(leukopenia, leukocyte count � 4000 cells/mm3;
thrombocytopenia, platelet count � 10000 cells/mm3;
and anemia, hemoglobin � 11 g/dL) and gastrointestinal (nausea/vomiting). Leukopenia was the most common side effect, occurring in 73.3% of patients treated.
Only 4 patients had Grade 3 leukopenia, and they recovered promptly with granulocyte-colony stimulating
factor (G-CSF ). Nausea/vomiting occurred in 39.3%
and was predominantly mild to moderate (up to Grade
2). Thrombocytopenia was observed in 32.1% and was
resolved without complications. The well-recognized
5-FU toxicities of diarrhea and hand- foot syndrome
were not observed, and stomatitis was infrequent
(7.1%). Nephrotoxicity and hepatotoxicity were not
observed. In general, no patients required treatment
interruption for toxicities.
DISCUSSION
A number of single agent chemotherapies for advanced gastric adenocarcinoma have resulted in low
response rates of 20 ? 30%.1,13 ? 15 The combination of
5-FU and methyl-CCNU16 and the combination of 5FU, doxorubicin, and BCNU17 have had initial response rates of 40% and 51%, respectively. However,
subsequent trials have failed to demonstrate any bene-
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CANCER July 1, 1997 / Volume 80 / Number 1
TABLE 3
Response Rate According to Performance Status, Histologic Type, and IAP
Overall
PS
0,1
2,3
Histology
Diff.
Undiff.
IAP
�0
�0
No. of
patients
CR
PR
SD
PD
Response
rate (%)
26
2
11
11
2
50.0
19
7
2
0
9
2
8
3
0
2
57.9
28.6
NS
10
18
1
1
6
5
2
9
0
2
77.8
35.3
NS
9
6
1
0
5
0
3
5
0
1
66.7
0.0
�05
P valuea
IAP: immunosuppressive acidic protein; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; PS: performance status; Diff.: differentiated type; Undiff.: undifferentiated type;
NS: not significant.
a
Based on chi-square test.
TABLE 4
Toxicities
Grade
Incidence of Grade 3 and 4
Toxicity
1
2
3
4
No. of patients
%
Nausea/Vomiting
Diarrhea
Stomatitis
Leukopenia
Anemia
Thrombocytopenia
Hepatotoxicity
Nephrotoxicity
Neurotoxicity
6
0
0
8
3
2
0
0
0
3
0
2
7
1
2
0
0
0
0
0
0
4
0
5
0
0
0
0
0
0
0
0
0
0
0
0
0/26
0/26
0/26
4/26
0/26
5/26
0/26
0/26
0/26
0
0
0
15.4
0
19.2
0
0
0
fit over single agents.18 5-FU, doxorubicin, and mitomycin C (FAM) was the most extensively used combination chemotherapy for gastric adenocarcinoma in
the 1980s, and this experience with over 400 patients
indicated a response rate of 33% and acceptable toxicity.19,20 Other combinations, including 5-FU, doxorubicin, and methotrexate (FAMTX)21 and 5-FU, doxorubicin, and BCNU (FEB),22 have demonstrated similar response rates to FAM.
Since cisplatin was reported to have activity
against gastric adenocarcinoma,23,24 several chemotherapies that have included cisplatin have shown superior response rates compared with previous regimens. Etoposide, doxorubicin, and cisplatin (EAP)
demonstrated a high response rate, including some
CR cases.25 ? 27 However, life-threatening toxicity with
EAP was also reported. More recent regimens have
been scheduled to maximize antitumor effects while
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minimizing toxicities.28 ? 30 For example, continuous infusion of 5-FU was more effective than bolus 5-FU in
the treatment of several advanced cancers, including
gastric adenocarcinoma.6 ? 9 In addition, MTX,31 leucovorin,32 and cisplatin33 ? 36 modulate antitumor effect
of 5-FU. Several experimental studies have revealed
synergism between 5-FU and cisplatin in vitro and
in vivo.4,5 Continuous infusion of 5-FU and cisplatin
infusion appears to be a promising combination.
The response rate in this study was 50%, which
was significantly superior to other two-drug combination chemotherapies excluding cisplatin and similar
or superior to multiple drug combinations, such as 5FU, doxorubicin, and mitomycin C (33%); 5-FU, doxorubicin, and MTX (50%); 5-FU, mitomycin C, and cytarabine (39%); 5-FU, doxorubicin, and carmustine
(42%); and etoposide, doxorubicin, and cisplatin
(64%).20,37 The median survival of patients in this
W: Cancer
5-FU and Cisplatin for Gastric Adenocarcinoma/Chung et al.
study was 7.3 months, which is similar or superior to
the survival of patients given other two-drug combinations (3.0 ? 7.7 months).20,37 In this study, liver metastases showed a lower response than primary lesions and
lymph node metastases. These results agree with those
reported previously.38
The high response rate in this study may be explained not only by the modulation of the pharmacologic effect of 5-FU by cisplatin but also by a direct
antitumor effect by cisplatin. In most combinations of
5-FU and cisplatin, cisplatin is given by bolus injection
once per week or course. In our protocol, cisplatin was
given daily for 5 days each week, for a total dose of
about 200 mg per course. Belliveau et al.39 have demonstrated that the area under the curve of the concentration of non-protein-bound cisplatin, which is related to the antitumor activity of cisplatin, was substantially higher in patients given continuous infusion
of cisplatin than after similar doses given as a bolus.
Moreover, Drewinko et al.40 have suggested that a protracted infusion of low dose cisplatin provides better
antitumor effects.
The toxicities we observed in this study were not
life-threatening and did not require treatment interruption or dose reduction. Although hydration to protect against nephrotoxicity due to cisplatin was not
given to all patients, nephrotoxicity was not observed.
Continuous infusion of 5-FU has resulted in lesser toxicities with a higher response rate than bolus 5-FU.9
Other studies41,42 in which continuous or prolonged
cisplatin infusion was given showed a lower degree of
toxicities accompanied by at least the same level of
efficacy as the bolus schedules. The reduced toxicities
of continuous cisplatin infusion may be related to reduced peak levels of filterable cisplatin.40,41
We examined several factors that influenced chemosensitivity to FP therapy. Several reports have
shown that the sensitivity of gastric adenocarcinoma
to various anticancer drugs did not correlate with several factors, including initial PS and histologic differentiation.43,44 In our study, patients with better PS (0 or
1) and differentiated histologic type showed a higher
response rate than patients with poor PS (2 or 3) and
undifferentiated histologic type, although there were
no significant differences. We also found that the response rates for patients with low serum levels of IAP
were higher than those for patients with high serum
levels of IAP. To the best of our knowledge, no previously published articles have mentioned the relationship between chemosensitivity and serum IAP levels. IAP was initially purified from the ascitic fluid
of patients with advanced cancer by Tamura et al.45
IAP is produced in T lymphocytes, B lymphocytes,
polymorphonuclear leukocytes, and macrophages,46
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5
and has various immunosuppressive effects on the
host immune system, such as suppression of natural
killer cell activity and modification of lymphocyte activity.47 ? 49 A clinical study has shown that gastric adenocarcinoma patients with high serum IAP levels have
higher risks of death from cancer and death from any
cause than patients with low serum IAP levels.50 It is
not clear why the response rates in patients with low
serum levels of IAP were higher than those in patients
with high serum levels of IAP. Other articles have
shown that protein-bound polysaccharide, which restores the suppressed immune response in a tumorbearing host, enhances the antineoplastic effects of
chemotherapeutic agents.51 The reserved immune response in a tumor-bearing host may be necessary for
chemotherapeutic agents to take sufficient effect in
vivo.
In conclusion, the combination of continuous
5-FU infusion and low dose cisplatin infusion for
the treatment of advanced and recurrent gastric adenocarcinoma seemed to be an effective regimen in
this study, with a high response rate and acceptable
toxicities, although a larger study will be necessary
to confirm the efficacy. In particular, the FP therapy
appeared to be useful for treating patients with IAP
values below the threshold (800 mg/mL).
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