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572
Phase II Trial of Trimetrexate for Patients with
Advanced Gastric Carcinoma
An Eastern Cooperative Oncology Group Study (E1287)
Ramesh K. Ramanathan, M.D.1
Stuart Lipsitz, Sc.D.2
Robert F. Asbury, M.D.3
Raman Qazi, M.D.4
Bernard R. Greenberg, M.D.5
Daniel G. Haller, M.D.6
1
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
2
Division of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Interlakes Oncology and Hematology P.C., New
York.
4
Highland Hospital, Rochester, New York.
5
University of Connecticut Health Center, Farmington, Connecticut.
6
University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania.
BACKGROUND. A Phase II study was conducted to evaluate the response, duration
of response, and duration of survival of patients with measurable gastric carcinoma
treated with trimetrexate (TMTX) who had not had prior chemotherapy.
METHODS. Thirty-three patients with unresectable or metastatic gastric adenocarcinoma who had not received previous chemotherapy were treated with intravenous TMTX 12 mg/m2 daily for 5 days. The dosage of TMTX was reduced to 8
mg/m2 daily for 5 days for those who had received prior radiotherapy. The cycle
was repeated every 3 weeks until disease progression or unacceptable toxicity
occurred.
RESULTS. Thirty-three patients could be analyzed with follow-up data. There was
one Grade 5 (lethal) toxicity and four Grade 4 toxicities. Hematologic toxicity was
the most common. The overall response rate was 21%, the overall median progression free survival was 2.7 months, and the overall median survival was 5.9
months for the entire cohort. No patients were alive at last follow-up.
CONCLUSIONS. Though TMTX as a single agent has activity in gastric carcinoma
with manageable toxicity, it cannot be recommended for routine use as a single
agent due to the brief duration of response and median survival. Cancer 1999;86:
572– 6. © 1999 American Cancer Society.
KEYWORDS: antifolates, gastric carcinoma, Phase II study, trimetrexate.
D
Supported in part by Public Health Service
grants CA18653, CA23318, CA07190, CA15488,
CA66636, and CA21115 from the National Cancer Institute, National Institutes of Health and
the Department of Health and Human Services.
This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D.,
Chair). Its contents are solely the responsibility of
the authors and do not necessarily represent the
official views of the National Cancer Institute.
Address for reprints: Ramesh K. Ramanathan, M.D.,
University of Pittsburgh Cancer Institute, N755 MUH,
200 Lothrop Street, Pittsburgh, PA 15213.
Received November 11, 1998; revision received
March 10, 1999; accepted March 10, 1999.
© 1999 American Cancer Society
espite its decreasing incidence, gastric carcinoma remains a significant cause of cancer death in the United States. In 1997, the
estimated incidence of gastric carcinoma was 22,400, with 14,000
deaths1. In patients who undergo surgical resection, there is no
known effective adjuvant therapy. Many chemotherapy agents have
been evaluated in this disease, with maximal response rates of '20%
reported for 5-fluorouracil (5-FU), adriamycin, mitomycin-C, methylCCNU, dacarbazine, carmustine, and hydroxyurea.2,3 In general, single agent therapy has been associated with short duration of response
and minimal impact on survival. Though numerous combination
regimens have been studied in advanced gastric carcinoma, most
regimens are associated with substantial toxicity, and their impact on
survival has not been significant. Therefore, there is a need to develop
new active agents in this disease.4 – 8
Trimetrexate (NSC-249008) (TMTX) was one in a series of nonclassical (i.e., without a glutamate residue) folate antagonists that
were developed originally as antimalarials but were found later to be
potent growth inhibitors of cultured tumor cells and more highly
concentrated in leukemia cells than methotrexate (MTX).9,10 Unlike
MTX, TMTX is more lipophilic and does not require activation by the
enzyme folylpolyglutamyl synthetase. It also differs from MTX in that
it does not require the reduced folate transport system to enter cancer
cells, thus avoiding competition for uptake when administered with
TMTX in Gastric Carcinoma/Ramanathan et al.
leucovorin.11,12 TMTX has demonstrated activity in
murine systems, including B16 melanoma, L1210 leukemia, P388 leukemia, and CD8F mammary carcinoma. The spectrum of this activity was greater than
that of MTX.13
In Phase I studies, the toxicities of TMTX included
myelosuppresion, nausea, mucositis, cutaneous toxicity, and renal dysfunction.14 The starting dose of
TMTX in solid tumors is 8 –12 mg/m2 given daily for 5
days, with cycles repeated every 3 weeks. The higher
dose of 12 mg/m2 is used in patients who were untreated previously.14
MATERIALS AND METHODS
Patients
Patients with surgically unresectable primary gastric
adenocarcinomas were eligible for this study. Patients
were required to have no previous chemotherapy. Previous radiation therapy to the indicator lesion was
allowed if there was documented growth of the lesion
on two consecutive evaluations resulting in a 25%
increase in the indicator lesion.
Histologic proof of residual, recurrent, or metastatic carcinoma was required, except in the case of
pulmonary metastases. Patients were required to have
an area of measurable, known malignant disease to
serve as an objective indicator of response to therapy.
Patients had a minimum of 3 weeks of recovery from
any major surgical procedure involving bypass, 2
weeks from exploration and biopsy only, and at least 4
weeks from any previous radiation. An Eastern Cooperative Oncology Group (ECOG) performance status of
0, 1, or 2 was required. Eligible patients had normal
bone marrow reserve (white blood cells [WBC] .
4000/mm3 and platelets . 150,000/mm3), renal function (blood urea nitrogen , 30 mg/dL or creatinine ,
1.5 mg/dL), and normal liver function (serum albumin . 3.0 gm/dL and total bilirubin , 1.5mg/dL).
All patients provided written, informed consent
conforming to federal and institutional guidelines. Patients with a prior history of malignant neoplasms
other than curatively treated basal cell or squamous
cell carcinoma of the skin or surgically cured carcinoma of the cervix in situ were ineligible for this study.
Patients with an active infectious process or malignant
effusions were ineligible.
Treatment Plan
The treatment schedule for TMTX consisted of 12
mg/m2 intravenously (IV) daily for 5 days. The doses
were diluted in D5W 100 ml and were infused over
10 minutes each day. The cycle was repeated every
3 weeks and was administered until there was disease progression, unacceptable toxicity, or patient
discontinuation. When the dosage was calculated,
573
the lesser of the ideal weight or the actual weight
was used to determine surface area. Patients who
had received prior radiation started therapy at 8
mg/m2 IV daily for 5 days. Patients were monitored
for adverse events, and therapy was repeated every
3 weeks if laboratory tests of bone marrow, kidneys,
and liver had normalized. If treatment was held for
more than 3 weeks, then patients were taken off of
the study. Dose modifications allowed for escalation
as well as reduction based on nadir counts. If WBC
was .3000/mm3 and platelets . 90,000/mm3, then
125% of the prior dose of TMTX was given. If nadir
counts of WBC were 2000 –2999/mm3and platelets
were 50,000 – 89999/mm3, then the dose was unchanged. If WBC , 2000/mm3 or platelets were
,50,000/mm3, then 50% of the prior dose of TMTX
was given. If mucositis was present on the day of
scheduled new course, then treatment was held until the mucositis had resolved. For Grade 3 mucositis
at any time, treatment was reinsituted at 75% of the
prior dose when mucositis had resolved. If serum
creatinine was ,1.5 mg/dL at the time of scheduled
therapy, then the dose of TMTX was unchanged;
however, if serum creatinine was in the range of
1.6 –2.0 mg/dL, then 50% of the prior dose was
given. If serum creatinine was .2.0 mg/dL, then
therapy was not given.
Patient Registration
The Central Randomization Desk randomized patients at the ECOG Operations Office over the telephone. Patients were stratified by performance status
(0 –1 vs. 2) and radiotherapy (prior vs. no prior). Written informed consent was required from all patients
prior to treatment assignment.
Accessibility Criteria
Patients were considered assessable for response if
they received at least one cycle of therapy. Tumor
response was classified as complete, partial, no
change, or progression. Complete response was defined as the complete disappearance of all measurable
or evaluable disease for at least 1 month. Partial response was defined as a minimum decrease of 50% in
the sum of the products of the greatest perpendicular
tumor dimensions and a definite improvement in
evaluable disease estimated .50% lasting at least 1
month. No change was defined as a decrease of ,50%
or an increase of ,25% in the sum of the products of
the greatest perpendicular tumor dimensions and no
change in evaluable disease lasting at least month.
Progression was defined as a minimum increase of
25% in the sum the of products of the greatest perpendicular tumor dimensions, an increase in the area
of evaluable disease estimated .25%, or the develop-
574
CANCER August 15, 1999 / Volume 86 / Number 4
ment of new lesions. Patients who relapsed had the
appearance of new measurable or evaluable disease,
an increase .25% over the minimum sum of the products of the greatest perpendicular tumor dimensions
during response, or an estimated increase of .25%
over the minimum area of evaluable disease during
response.
Statistical Analysis
Fisher’s exact test was used to analyze contingency
tables of response. Survival curves were estimated by
using the method of Kaplan and Meier,15 with differences assessed by using the log-rank test.16 Logistic
regression17 of response and proportional hazards regression18 of survival to identify simultaneously significant prognostic covariates were based on the likelihood ratio test. To calculate confidence intervals for a
binomial parameter for a two-stage, Phase II clinical
trial, we used the method of Atkinson and Brown.19
RESULTS
Administrative Information
The protocol was activated in September 1987, with an
accrual goal of 32 patients (30 evaluable) with gastric
carcinoma to be entered by the 23 participating institutions. In May 1988, the study was redesigned as a
two-step study and also added the site of small bowel
carcinoma as another stratum. The first stage of the
new design had separate accrual goals of 15 evaluable
patients in the 2 disease sites. After accruing 15 evaluable patients in a given site, if 3 or more responses
were seen, then the accrual was to be extended for
another 15 evaluable patients. There were 3 responses
in the first 15 patients with gastric carcinoma, and
accrual continued until September 1989. In October
1989, after having accrued only 2 small bowel patients,
the study was closed to small bowel patients because
of poor accrual. The ineligibility rate was low, with the
1 ineligible patient having small bowel carcinoma and
nonmeasurable disease.
TABLE 1
Patient Characteristics on Study
Characteristic
Age (yrs)
Median (range)
Performance status
ECOG 0–1
ECOG 2
Gender
Female
Male
Prior Radiotherapy
Yes
No
Total
(%)
62 (46–83)
—
29
4
88
12
7
26
21
79
1
32
3
97
ECOG: Eastern Cooperative Oncology Group.
patient died 26 days after treatment was stopped. The
adverse drug report states “microangiopathic hemolytic anemia probably associated with diffuse bone
marrow disease, and probably not drug related.”
There have been four Grade 4 hematologic toxicities,
all leucopenia in nature. Table 2 summarizes the incidence of toxicities related to therapy, which ranged
from none to lethal in nature. Hematologic toxicity,
leucopenia in particular, was the most common toxicity.
Response
A total of 7 patients had complete or partial responses.
Objective response data are summarized in Table 3.
Three patients had a complete response with sites of
disease in the liver and the lymph nodes and a soft
tissue mass. The overall response rate was 21% (7 of 33
evaluable patients). A 90% confidence interval for the
probability of response in the gastric patients, using
the method described by Atkinson and Brown,19 was
11.3–39.4%. The median response duration for the 7
patients with responses was 6 months, with durations
ranging from 1 month to 11.5 months.
Patient Characteristics
Progression Free Survival
Thirty-three patients with gastric adenocarcinoma
were accrued. None had received prior chemotherapy.
One patient had received previous radiotherapy. The
median age was 62 years. Table 1 summarizes the
distribution of patient characteristics from the study,
including the stratification factors.
Progression free survival time was computed from
randomization to progression or death, which ever
came first, or was censored at the time last known
alive without progression. Of the 33 patients who
could be analyzed, all have died. The overall median
progression free survival was 2.7 months. The analysis
of single covariates shows that disease free survival
was related significantly only to performance status
(P 5 0.05).
Toxicity
Toxicity was evaluated on all 33 patients. One patient
had a lethal toxicity. In this patient, treatment was
stopped after one cycle (Day 8) due to severe anemia
(hemoglobin 5 3.1 gm/dL). The patient received
transfusions, but blood counts remained low, and the
Survival
Survival time is computed from randomization to
death or is censored at the time last known alive. The
TMTX in Gastric Carcinoma/Ramanathan et al.
575
TABLE 2
Treatment-Related Toxicities According to Eastern Cooperative Oncology Group Toxicity Criteria
Grade
Toxicity
1
2
3
4
5
Gastrointestinal
Vomiting
Diarrhea
Infection
Hemorrhage
Skin, mucous membrane
Neurologic
Genitourinary
Hematologic
Liver
Othera
7
6
7
—
—
7
6
7
4
1
7
4
8
—
4
—
5
5
—
—
1
2
1
4
—
—
6
—
2
—
—
—
—
—
—
—
—
4
—
—
—
—
—
—
—
—
—
—
1
—
—
a
11
2
5
The Grade 3 others were cardiac.
TABLE 3
Objective Response
Response
Total no.
%
Complete response
Partial response
No change
Progression
Unevaluablea
Cases analyzed
3
4
2
22
2
33
9
12
6
65
9
100
a
Unevaluable for response (1 patient had inadequate follow-up, and 1 patient was taken off the study
due to toxicity after 1 cycle).
overall median survival was 5.9 months. All patients
have died.
DISCUSSION
Patients with advanced gastric carcinoma have a poor
prognosis. The median survival in this group of patients is in the range of 5–10 months, and few untreated patients survive more than 1 year after initial
diagnosis. 5-FU is the single most extensively studied
agent in this disease, with a response rate of 21%.20
Among the newer agents, docetaxel has shown single
agent activity of 14% and currently is being studied in
combination with platinum and other agents.21 However, complete responses with single agent therapy are
rare, and response duration generally is brief, without
any appreciable improvement in overall survival. In
this study, single agent TMTX showed a response rate
of 21% in patients with gastric adenocarcinoma. The
response rate in patients with small bowel adenocarcinoma could not be assessed due to poor accrual and
early closure of the study to this site. The activity of
TMTX in this study is comparable to other single
agents in this disease. There is only one other study
evaluating TMTX in advanced gastric carcinoma. The
Southwest Oncology Group used a similar dose schedule of TMTX (8 –12 mg/m2/day for 5 days). A response
rate of 4% was reported (95% confidence interval,
0 –22%), and the median survival was 6 months. These
results are comparable to our study, in which the
response rate was 21% (90% confidence interval, 11.3–
39.4%), and the median survival was 5.9 months. Hematologic toxicity, similar to our report, also was predominant, with Grade 3 toxicity seen in 10 out of 23
patients.
In general, as a single agent, the activity of TMTX
in various solid tumors has been modest, with response rates generally '10%.14 It appears that the
combination of TMTX and 5-FU may be more active
than either drug alone. Studies suggest that TMTX
may modulate the activity of 5-FU and enhance its
cytotoxicity.23,24 The sequence of 5-FU and TMTX administration appears to be important, because synergistic cytotoxicity was seen when TMTX was added
before 5-FU. When the sequence was reversed and
5-FU was given before TMTX, antagonism was observed.25 The mechanism of synergy is thought to be
due to increased intracellular accumulation of 5-phosphoribosyl-1-pyroposphate caused by antifolate inhibition of purine synthesis.25 In cell lines, 5-FU and
leucovorin showed increased cytotoxicity in the presence of TMTX, which was greater than the combination of 5-FU and TMTX alone.26 Based on these observations, trials of the combination TMTX, 5-FU, and
leucovorin have been conducted.27–29. In colorectal
carcinoma, this regimen has shown activity in both
untreated and previously treated patients.27–29 Gastrointestinal toxicity, in particular diarrhea, appears to be
the most significant toxicity of this regimen, and this
576
CANCER August 15, 1999 / Volume 86 / Number 4
may be ameliorated by a high dose loperamide regimen.
We do not recommend the use of single agent
TMTX in gastric carcinoma due to the brief duration of
response and median survival. However, further evaluation of TMTX with 5-FU and leucovorin is warranted, because this regimen has sound preclinical
rationale as well as encouraging activity in colorectal
carcinoma.
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