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A Phase II Study of 5-Fluorouracil, Leucovorin, and
Interferon-␣ in the Treatment of Patients with
Metastatic or Recurrent Gastric Carcinoma
An Eastern Cooperative Oncology Group Study (E5292)
Gary R. Hudes, M.D.1
Stuart Lipsitz, Sc.D.2
Jean Grem, M.D.3
Mary Morrisey, Sc.D.2
Louis Weiner, M.D.1
John W. Kugler, M.D.4
Al Benson III, M.D.5
Department of Medical Oncology, Fox Chase
Cancer Center, Philadelphia, Pennsylvania.
Division of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Medicine Branch, National Cancer Institute, National Naval Medical Center, Bethesda, Maryland.
Illinois Oncology Research Association, Peoria,
Division of Hematology/Oncology, Northwestern
University Medical Center, Chicago, Illinois.
Presented in part at the 31st Annual Meeting of the
American Society of Clinical Oncology, Los Angeles
California, May 20 –23, 1995.
This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D.,
Chair) and supported in part by Public Health
Service Grants CA18281, CA23318, CA21076,
CA17145, CA66636, and CA21115 from the National Cancer Institute, National Institutes of
Health, and the Department of Health and Human
Address for reprints: Gary R. Hudes, M.D., Department of Medical Oncology, Fox Chase Cancer Center,
7701 Burholme Avenue, Philadelphia, PA 19111.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer
Received February 12, 1998; revision received
June 2, 1998; accepted June 26, 1998.
© 1999 American Cancer Society
BACKGROUND. Chemotherapy has a limited impact on adenocarcinoma of the
stomach. Although biochemical modulation of 5-fluorouracil (5-FU) by leucovorin
(LV) and interferon-␣ (IFN-␣) has improved the outcomes of patients with metastatic colorectal carcinoma compared with 5-FU alone, this approach has not been
extensively evaluated in the treatment of advanced gastric carcinoma.
METHODS. Twenty-seven patients with bidimensionally measurable, metastatic
gastric carcinoma and an Eastern Cooperative Oncology Group performance status
of 0 or 1 received the combination of IFN-␣ (5 million U/m2 administered subcutaneously daily on Days 1–7), LV (500 mg/m2 administered intravenously over 30
minutes immediately after IFN-␣ on Days 2– 6), and 5-FU (370 mg/m2 given as an
intravenous bolus 60 minutes after LV on Days 2– 6), with treatment repeated every
4 weeks. Oral cryotherapy was administered routinely before each dose of 5-FU to
reduce the incidence of severe stomatitis.
RESULTS. The median age of the patients was 58 years (range, 20 –76), and 22
patients had residual, unresectable primary lesions. The median number of cycles
received was 3 (range, 1–11). Of 24 patients who received at least 2 cycles of
treatment, 15 (62.5%) did not require dose reduction for toxicity during the initial
2 cycles. The predominant toxicities were gastrointestinal: diarrhea and stomatitis
of Grade 3– 4 occurred in 28.6% and 35.7% of patients, respectively. Other severe
(Grade 3– 4) toxicities were granulocytopenia (which occurred in 21.4% of patients)
and fatigue (in 10.7%). Fever and flu-like symptoms were common but usually
mild. Of 24 patients who were evaluable for response, 3 had partial responses (PR)
of 16, 23, and 33 weeks’ duration, respectively, for a response rate of 12.5% (95%
confidence interval ⫽ 2.7–32.4%). Two additional patients had reductions in tumor
size sufficient for PR, but scans to document the minimum required response
duration of 4 weeks were not obtained before progressive disease occurred. The
median progression-free and overall survivals were 2.5 and 7.8 months, respectively.
CONCLUSIONS. Although this regimen can be administered safely with appropriate
supportive care to patients with good performance status, it has limited therapeutic activity in patients with advanced gastric carcinoma. Cancer 1999;85:290 – 4.
© 1999 American Cancer Society.
KEYWORDS: gastric carcinoma, 5-fluorouracil, interferon, chemotherapy.
lthough declining in incidence, adenocarcinoma of the stomach
remains a significant cause of cancer death in the U. S. and the
second leading cause of cancer death worldwide. Approximately 50%
of patients with this malignancy present with tumors that are locally
5-FU, LV, and IFN-␣ in Gastric Carcinoma/Hudes et al.
advanced or metastatic, considered beyond the hope
of curative surgical resection. The impact of systemic
chemotherapy in adenocarcinoma of the stomach has
been minimal, with median survival unaffected by
currently available agents and combinations.1 There is
a great need to identify more active agents and combinations for the treatment of patients with metastatic
disease, and for those patients with resectable tumors
who could benefit from effective adjuvant therapy to
decrease the risk of tumor recurrence.
When administered as a single agent, 5-fluorouracil (5-FU) has generated objective regressions in approximately 20% of patients with advanced gastric
carcinoma.2 The biochemical modulation of 5-FU by
leucovorin (LV) and interferon-␣ (IFN-␣) has been
associated with improved response rates in patients
with metastatic colorectal carcinoma.3,4 The activity of
the 5-FU and LV and 5-FU and IFN-␣ regimens
prompted investigation of a three-drug regimen of
5-FU, LV, and IFN-␣ as described by Grem et al.5 The
combination of 5-FU, LV, and IFN-␣ produced a 54%
partial response rate in a Phase II trial involving 44
patients with colorectal carcinoma.6 Biochemical
modulation of 5-FU has been evaluated less extensively in gastric carcinoma. Based on the promising
results reported in colorectal carcinoma, a Phase II
trial of 5-FU, LV, and IFN-␣ in patients with adenocarcinoma of the stomach was initiated by the Eastern
Cooperative Oncology Group (ECOG). The objectives
of this trial were: 1) to determine the response rate,
time to progression, and survival in patients with advanced gastric carcinoma treated with recombinant
IFN-␣-2b given on Days 1–7 in combination with bolus 5-FU/LV given on Days 2– 6; 2) to evaluate all
toxicities of the combination of 5-FU, LV, and IFN␣-2b in this patient population; and 3) to determine
the dose intensity of 5-FU given with LV and IFN-␣-2b
on this schedule in a homogenous patient population
with no prior chemotherapy for metastatic or recurrent disease.
Between November 1992 and September 1993, 28 patients from 17 ECOG institutions were enrolled on this
Phase II trial. Eligibility for the trial required histologically proven advanced or metastatic adenocarcinoma
of stomach (excluding patients with tumors of the
distal esophagus or gastroesophageal junction) considered beyond the hope of cure by surgical resection;
at least 1 metastatic site measurable in 2 dimensions;
no prior chemotherapy for metastatic disease and at
least 1 year between the completion of adjuvant chemotherapy and protocol entry; an ECOG performance
status of 0 or 1; adequate caloric intake and estimated
life expectancy of at least 3 months; a leukocyte
count ⱖ 4000/␮L or granulocyte count ⱖ 2000/␮L,
platelets ⱖ 100,000/␮L, serum creatinine ⱕ 2.0 mg/dL,
total bilirubin ⱕ 2.0 mg/dL, and aspartate aminotransferase (AST) ⱕ 4 times the upper limit of normal.
Written informed consent was obtained from each
patient according to institutional and federal guidelines.
Patients had the following evaluations before
treatment: history and physical examination, weight,
ECOG performance status, complete blood count, serum creatinine, alkaline phosphatase, AST, total bilirubin, chest radiograph, and computed tomography
(CT) scans or other imaging studies as needed for
disease measurement. Premenopausal females were
required to have a negative serum pregnancy test.
Patients and caregivers were instructed on subcutaneous injection technique prior to beginning treatment.
Weight, performance status, and complete blood
counts were repeated weekly during protocol therapy.
Creatinine and other chemistries were repeated prior
to each subsequent course (every 4 weeks), and CT
scans and other studies for assessment of response
were obtained every 2 courses.
Treatment was comprised of recombinant IFN␣-2b (Intron-A; Schering, Kenilworth, NJ) administered subcutaneously at a dosage of 5 ⫻ 106 U/m2
daily on Days 1–7 of each 4-week cycle. Patients or
family members were instructed on the administration technique to permit home administration of the
IFN-␣ on Days 1 and 7. On Days 2– 6, patients received
calcium LV at a dosage of 500 mg/m2 by intravenous
infusion over 30 minutes immediately after IFN-␣.
5-FU was given at a dosage of 370 mg/m2 by bolus
injection 60 minutes after completion of each LV infusion on Days 2– 6. The treatment was repeated every
28 days provided toxicity had resolved. In view of the
potential for severe gastrointestinal toxicity from the
treatment, the following supportive care measures
were required: 1) patients were educated regarding
the need for prompt notification of the treating physician if mouth pain and/or diarrhea occurred; 2) prophylaxis against stomatitis included oral cryotherapy7
with each dose of 5-FU, sodium bicarbonate mouth
rinses, and oral antimicrobial rinses with chlorhexidine; 3) for Grade 1–2 diarrhea, early intervention was
comprised of antidiarrheal medication, instructing patients to increase fluid intake, and treatment of stomatitis, if present, to permit continued oral intake.
Toxicity was graded according to the common
toxicity criteria (Cancer Therapy Evaluation Program
[CTEP]) and response was assessed by ECOG solid
tumor response criteria.8 Treatment was modified for
toxicity according to the following. Subsequent
CANCER January 15, 1999 / Volume 85 / Number 2
courses of treatment were delayed up to 3 weeks for
Day 1 absolute granulocyte count (AGC) ⬍ 1500/␮L or
platelet count ⬍ 80,000/␮L. For nadir blood counts,
the dose of 5-FU was reduced by 25% for AGC ⬍
500/␮L or platelet count ⬍ 25,000/␮L.
For any grade of diarrhea or the appearance of ⱖ
Grade 2 stomatitis (oral ulceration) during the 5 days
of therapy administration, treatment was discontinued for that cycle. In addition, the dose of 5-FU was
reduced by 25% for diarrhea or mucositis of Grade 3 or
4 occurring at any time. A 25% reduction of IFN-␣ was
permitted for intolerable constitutional symptoms
such as fatigue, malaise, arthralgia, myalgia, or anorexia.
Study Design and Statistical Considerations
The primary endpoint was tumor response. A twostage design was utilized so that the trial could be
stopped early if the treatment did not produce a response rate consistent with known combinations of
5-FU. The response rate of interest was 40%. If there
were ⱕ 4 responses (complete or partial responses)
among the initial 20 evaluable patients, then the treatment would be considered not sufficiently promising.
If ⱖ 5 responses were observed among the initial 20
eligible patients, an additional 22 patients could be
The probability that the trial would be stopped
early (i.e., ⱕ 4 responses in the first 20 eligible patients) was approximately 0.051 if the true response
rate was at least 40%. If the trial continued to 40
patients and at least 13 responses were observed, then
the treatment would be considered promising and the
90% confidence interval (95% CI) for the true response
rate would be 20 – 47%.
The study was opened in November of 1992 and was
closed in August 1993, having met and exceeded the
first stage accrual of patients. The study was terminated due to an insufficient number of responses in
the first stage.
Patient characteristics are summarized in Table 1.
A total of 28 patients were registered, 24 of whom were
eligible and evaluable for toxicity and response. Four
patients were not evaluable for the following reasons:
2 patients had primary gastroesophageal junction tumors and were ineligible, 1 patient lacked measurable
disease, and 1 patient withdrew from the protocol
after only 1 day of treatment. All 28 patients were
evaluable for toxicity. A total of 102 cycles of therapy
were administered, with a median of 3 cycles per
patient (range, 1–11). Fifteen patients (62.5%) received
Patient Characteristics
No. (%)
Total registered
Total eligible
Evaluable for response
Evaluable for toxicity
ECOG performance status
Median age (yrs) (range)
Prior therapy
Sites of measurable disease
Lymph nodes
Other soft tissue
Median no. of cycles (range)
58 (20–76)
3 (1–11)
ECOG: Eastern Cooperative Oncology Group.
the full planned dose intensity of all drugs during the
initial 2 cycles.
Of the 24 patients evaluable for response, 3 had
partial responses lasting 16, 23, and 33 weeks, respectively, for a response rate of 12.5% (95% CI, 2.7–32.4%).
The sites of response were the liver in two patients and
the lymph nodes in one patient. Two additional patients had ⱖ 50% decrease in tumor size after 2 cycles
of treatment, but could not be considered partial responders by the protocol criteria because repeat CT
scans were not performed to document a response
duration of at least 4 weeks. One of these patients had
a 50% reduction in retroperitoneal lymph nodes and
experienced Grade 2 nausea, emesis, diarrhea, and
stomatitis. This patient refused further treatment and
presented 1 year later for terminal care. The second
patient had an 80% reduction in liver metastases and
retroperitoneal adenopathy, but developed progressive disease in the liver 2 months later. A CT scan to
confirm a response duration of at least 4 weeks was
not obtained. The remaining 19 patients had disease
progression at a median of 2.5 months from protocol
entry. The median survival of all registered patients
was 7.7 months.
Toxicity is summarized in Table 2. The principal
toxicities were granulocytopenia, stomatitis, and diarrhea. Grade 3 or 4 granulocytopenia occurred in 7
patients (25%). Documented sepsis or other infection
occurred in four patients. Thrombocytopenia and
anemia were mild. Despite oral cryotherapy in all but
5-FU, LV, and IFN-␣ in Gastric Carcinoma/Hudes et al.
Toxicity (Worst Grade) (N ⴝ 28)
Weight loss
Flu-like reaction
Grade 3/4
5 of the patients, 10 patients (35.7%) experienced
Grade 3 or 4 stomatitis during treatment, most commonly during Cycles 1 or 2. There was no correlation
between oral cryotherapy and the severity of stomatitis. Grade 3 or 4 diarrhea occurred in eight patients.
Grade 2 or 3 fatigue occurred in five and three patients, respectively. Flu-like symptoms resulting from
administration of IFN-␣ were common but usually
mild. There was one episode of Grade 4 dermatologic
toxicity comprised of scrotal erythema and sloughing.
Toxicity prompted reduction of the 5-FU dose for the
first or second treatment cycle in seven patients. The
dose of IFN-␣ was reduced by 25% for 2 patients. Only
2 patients required a delay in treatment for the first 2
cycles, both for 1 week, to allow recovery from toxicity.
schedule described in this Phase II trial does not merit
further study in patients with gastric carcinoma. These
results differ from those of Jäger et al., who observed
10 complete responses and 20 partial responses for a
total of 30 objective responses in 72 patients (42%;
95% CI, 28 –57%) utilizing 5-FU, 500 mg/m2, bolus
together with LV, 500 mg/m2, over 2 hours and IFN-␣
6 ⫻ 106 U subcutaneously, with all agents given once
a week.14 These authors reported that the median time
to progression and survival were 6 and 9 months,
respectively. It is interesting to note that the myelotoxicity and gastrointestinal toxicity reported by Jäger
et al. appeared to be less than those observed in the
current study. The reason for the different levels of
activity in the current study and that of Jäger et al. is
not clear. Although the schedules differed significantly, the dose intensities of 5-FU and IFN-␣ per
4-week cycle were similar in the 2 studies.
With appropriate supportive care, the combination of 5-FU and LV daily for 5 days and IFN-␣ daily for
7 days can be administered safely to patients with
advanced gastric carcinoma and a good ECOG performance status. However, this combination has limited
activity and cannot be recommended as conventional
therapy for this tumor. The results of this trial do not
suggest that the combination is likely to offer more
benefit than the combination of 5-FU and LV.
Effective treatment for metastatic gastric carcinoma
has been elusive. Combination therapies that employ
two or more of the known active agents have failed to
extend the median survival of patients with this tumor. In contrast to colorectal carcinoma, there has
been little evidence that biochemical modulation of
5-FU by LV or IFN-␣ improves on the estimated 20%
response rate and 5– 6-month median survival of single agent 5-FU in patients with advanced/metastatic
gastric carcinoma. The combination of 5-FU plus LV
has produced responses in 8 – 48% of patients with
advanced/metastatic gastric carcinoma in several
small trials utilizing a variety of schedules.9 –12 The
median survival of patients in these trials has ranged
from 4.8 –5.5 months. Similarly, in the Phase II trial of
5-FU plus IFN-␣ reported by Pazdur et al., the objective response rate of 25% and median survival of 7
months was not clearly better than 5-FU alone.13
We believe the observed 12.5% response rate of
the 5-FU, LV, and IFN-␣ combination utilizing the
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RB, Oishi N, et al. Phase II study of 5-fluorouracil and folinic
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