Download Phase II trial of 5-fluorouracil plus eniluracil in patients with

Original article
Annals of Oncology 13: 1576–1582, 2002
DOI: 10.1093/annonc/mdf274
Phase II trial of 5-fluorouracil plus eniluracil in patients with
advanced pancreatic cancer: a Southwest Oncology Group study
M. L. Rothenberg1*, J. K. Benedetti2, J. S. Macdonald3, T. E. Seay4, M. A. Neubauer5, C. S. George6,
M. S. Tanaka Jr7, J. K. Giguere8, B. T. Pruitt9 & J. L. Abbruzzese10†
1
Vanderbilt University Medical Center, Nashville, TN; 2Southwest Oncology Group Statistical Center, Seattle, WA; 3St Vincent’s Comprehensive Cancer Center,
New York, NY; 4Atlanta Regional Community Clinical Oncology Program, Atlanta, GA; 5Kansas City Community Clinical Oncology Program, Kansas City, MO;
6
Columbus Community Clinical Oncology Program, Columbus, OH; 7University of California, Davis, Sacramento, CA; 8Greenville Community Clinical
Oncology Program, Greenville, SC; 9Don and Sybil Harrington Cancer Center, Amarillo, TX; 10University of Texas, M.D. Anderson Cancer Center,
Houston, TX, USA
Received 31 January 2002; revised 4 April 2002; accepted 24 April 2002
Background: Eniluracil is a potent, irreversible inactivator of dihydropyrimidine dehydrogenase, the
major catabolic enzyme for 5-fluorouracil (5-FU). Pretreatment with eniluracil significantly increases
plasma half-life, plasma concentration and oral bioavailability of 5-FU. This multicenter phase II trial
was designed to estimate the 6-month survival rate in patients with metastatic adenocarcinoma of the
pancreas treated with 5-FU and eniluracil.
Patients and methods: One hundred and sixteen patients (61 with no prior chemotherapy and 55 with
prior chemotherapy) were registered for treatment with eniluracil 50 mg (total dose) p.o. on days 1–7
and 5-FU 20 mg/m2/day p.o. on days 2–6 of a 28-day treatment cycle.
Results: In 106 patients evaluable for survival, the 6-month survival rate was 34% [95% confidence
interval (CI) 22% to 47%, median survival 3.6 months] for patients who had not been treated previously
with chemotherapy and 29% (95% CI 16% to 42%, median survival 3.4 months) for those who had
received prior chemotherapy. For those patients with measurable disease, the confirmed response rates
were 8% and 2%, respectively. The most common grade 3–4 toxicities were neutropenia (29% of
patients) and diarrhea (12% of patients). Overall, 69% of patients experienced a grade 3 or worse
adverse event during treatment.
Conclusions: These results suggest that the combination of a 7-day course of eniluracil and a 5-day
course of oral 5-FU has limited activity in patients with advanced pancreatic cancer, and is associated
with a high frequency of clinically significant adverse events.
Key words: 5-fluorouracil, clinical trial, eniluracil, oral chemotherapy, pancreatic cancer, phase II
Introduction
Pancreatic cancer is one of the leading causes of cancer-related
death in the United States; it is estimated that 28300 people
died from cancer of the pancreas in 2000 [1]. Eighty to 90% of
patients have unresectable disease at the time of diagnosis. For
many years, 5-fluorouracil (5-FU) was the primary therapy for
patients newly diagnosed with advanced stage disease. The
activity reported for 5-FU in this setting has been highly
variable, with objective response rates ranging from 0% to
*Correspondence to: Dr M. L. Rothenberg, Vanderbilt University
Medical Center, 777 Preston Research Building, Nashville,
TN 37232-6307, USA. Tel: +1-615-343-8422; Fax: +1-615-343-7602;
E-mail: [email protected]
†Reprint requests to: Southwest Oncology Group (SWOG-9629),
Operations Office, 14980 Omicron Drive, San Antonio,
TX 78245-3217, USA.
© 2002 European Society for Medical Oncology
>20% in phase II trials [2]. Despite numerous attempts to
improve the efficacy of 5-FU through biochemical modulation, the addition of other cytotoxic drugs or an alteration to
the drug administration schedule, no maneuver consistently
resulted in improved overall survival above that attained with
single-agent 5-FU. More recently, the use of 5-FU in this
setting has declined due to the results of a phase III study that
demonstrated the superiority of gemcitabine over 5-FU in the
treatment of patients with newly diagnosed, advanced stage
pancreatic cancer in terms of survival (median survival
5.65 months compared with 4.41 months in 5-FU-treated
patients) and relief from tumor-related symptoms (clinical
benefit response rate 23.8% compared with 4.8%) [3]. The
6-month survival rate was 46% for patients who received
gemcitabine and 31% for those treated with 5-FU.
Eniluracil (5-ethynyluracil, BW776C85, GW776C85, 776C85; GlaxoSmithKline, Collegeville, PA) is a potent, irrevers-
1577
ible inactivator of dihydropyrimidine dehydrogenase (DPD),
the rate-limiting enzyme in the breakdown of 5-FU [4]. Pretreatment with eniluracil significantly increases the plasma
half-life as well as the plasma concentration and duration (i.e.
area under the concentration–time curve) of 5-FU. Production
of inactive catabolites of 5-FU that may interfere with the
antitumor activity of 5-FU, such as α-fluoro-β-alanine and
5-H2-FU, are reduced by pretreatment with eniluracil [4].
Eniluracil converts 5-FU from a drug that is enzymatically
catabolized to one that is dependent upon renal clearance as its
primary mode of drug elimination. Preclinical studies demonstrated that eniluracil markedly improved the complete remission rate from 14% to 100%, and improved the therapeutic
index of 5-FU from 1.0 to 6.0 in rats bearing Ward colorectal
carcinomas [5]. Given this enhanced activity against a murine
tumor with minimal sensitivity to single agent 5-FU, we felt
that it would be of interest to evaluate the combination of eniluracil and 5-FU in patients with advanced adenocarcinomas
of the pancreas.
Two schedules of the 5-FU + eniluracil combination were
brought forward into phase II testing: (i) a shorter schedule
consisting of a 5-day course of 5-FU with a 7-day course of
eniluracil and (ii) a longer schedule consisting of a 28-day
course of both drugs [6, 7]. The shorter schedule was designed
to mimic the 5-day course of intravenous 5-FU (Mayo Clinic
schedule) that was popular in the United States in the 1980s
and 1990s. It was this shorter schedule that was selected for
evaluation in this clinical trial.
Phase II trials of new agents are often designed around a
primary end point of objective response rate as a method of
identifying agents with sufficient activity to warrant further
clinical evaluation. Unfortunately, pancreatic cancer does not
fit easily into this paradigm. Pancreatic cancer is notoriously
difficult to measure precisely in anatomic imaging studies,
using CT or MRI for example [8]. This is probably one of the
main reasons why high response rates in some phase II trials
fail to translate into an improvement in survival in phase III
trials.
Published survival data for patients treated with gemcitabine
in phase II and III trials, as well as in the investigational new
drug (IND) treatment program, has been fairly consistent [3, 9,
10, 20]. The median survival in patients with advanced
pancreatic cancer who received gemcitabine as first-line
chemotherapy is 5.1–6.3 months, and the 6-month survival
rate is 46–52% [3, 10, 20]. For those patients who receive
gemcitabine as second-line chemotherapy, median survival is
3.9–4.4 months, with a 6-month survival rate of ∼31% [9, 10].
This consistency in survival data, coupled with the unreliability of anatomical imaging studies, prompted us to design
this phase II trial of oral 5-FU and eniluracil around a primary
end point of 6-month survival rate rather than objective
response rate.
Patients and methods
Patients were required to meet the following eligibility criteria: (i) cytologically or pathologically verified diagnosis of pancreatic adenocarcinoma that was metastatic at the time of registration; (ii) bidimensionally
measurable or evaluable disease; (iii) Southwest Oncology performance
status of 0–2; (iv) calculated creatinine clearance of ≥50 ml/min using the
Cockroft–Gault formula; (v) no more than one prior chemotherapy regimen
for metastatic pancreatic cancer; and (vi) the ability to swallow and retain
oral medications. Prior treatment with 5-FU or mitomycin-C as a single
agent or as part of a combination regimen was not permitted. If the patient
had been treated previously for pancreatic cancer, there must be current
evidence of progressive disease. Prior radiotherapy and surgery were
permitted if completed at least 4 weeks prior to registration. Informed
consent was obtained from all patients in accordance with institutional
and federal guidelines prior to the initiation of treatment.
Treatment
Treatment consisted of eniluracil 50 mg (total dose/day) p.o. qd (days 1–7)
and 5-FU 20 mg/m2/day p.o. qd (days 2–6) as part of a 28-day treatment
cycle. Patients took eniluracil tablets immediately before 5-FU tablet(s)
on days 2–6. Patients fasted for 1 h prior to the dose of eniluracil and for
1 h after the dose of 5-FU.
To begin the next course of treatment, patients were required to have a
platelet count ≥75 000/mm3, granulocytes ≥1500/mm3, and resolution of
clinically significant non-hematologic toxicities to no more than grade 1.
Dose modification of 5-FU was based upon the maximum intensity of
drug-related toxicities occurring in the previous course [21]. Dose was
calculated as a percentage of the previous dose of 5-FU and rounded to the
nearest 5 mg. The dose of 5-FU was reduced by 20% for grade 3–4
hematologic toxicity, except in the case of grade 4 neutropenia with fever
or infection, or grade 4 thrombocytopenia, when the dose of 5-FU was
reduced by 40%. Treatment was not given to any patient whose creatinine
clearance fell to <40 cc/min. Patients with a creatinine clearance of
40–49 cc/min received 80% of their previous dose. 5-FU was reduced by
20% for any other grade 2–3 non-hematologic toxicity, and reduced
by 40% for any grade 4 non-hematologic toxicity. Dose reductions for
nausea, vomiting or diarrhea were made only if they occurred despite
appropriate supportive measures. Patients who were dose reduced and
developed no grade 2 or worse toxicity could receive the next cycle of
treatment at a 20% dose escalation. The highest dose of 5-FU permitted
was the original dose. No modification was made to the eniluracil dose for
any toxicity.
Evaluation
Patients were monitored with a complete blood count and toxicity
assessment every 2 weeks, a physical examination every 2 weeks during
the first cycle of therapy and then every 4 weeks thereafter, and estimated
creatinine clearance, total bilirubin and AST (SGOT) or ALT (SGPT)
every 4 weeks just prior to a new cycle of treatment. Tumor assessment
was performed every 8 weeks. Treatment continued until disease progression, the appearance of unacceptable toxicity, a delay in initiation of a
new cycle of therapy by ≥3 weeks due to toxicity, withdrawal of patient
consent, or death.
Statistical analysis
The primary objective of this study was to evaluate the 6-month overall
survival rate in patients with pancreatic cancer treated with oral 5-FU +
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eniluracil. Because it was assumed that patients who had received prior
chemotherapy would have a poorer prognosis, accrual proceeded independently for those patients who were chemotherapy naïve and those who
had received prior treatment with gemcitabine. In the chemotherapy naïve
group, it was assumed that the combination of oral 5-FU and eniluracil
would not be of further interest if the 6-month survival rate was ≤35%, but
of considerable interest if it was ≥55%. These assumptions were based on
the 46% 6-month survival rate observed for gemcitabine-treated patients
in the original phase III trial and a similar survival rate achieved in previously untreated patients who received gemcitabine under the IND treatment [3, 10]. The accrual goal was 55 evaluable patients. Twenty-six or
more patients surviving past 6 months would be considered evidence of
the need for further study of this regimen. This design has a significance
level (i.e. probability of declaring an agent with a 35% true 6-month
survival rate as warranting further study) of 0.04 and a power (probability
of correctly declaring an agent with a 55% true 6-month survival rate as
warranting further study) of 0.90.
Among patients who received 5-FU and eniluracil as second-line
chemotherapy, it was assumed that this regimen would not be of further
interest if the true 6-month survival rate was ≤20%, but of considerable
interest if it was ≥40%. These assumptions were based on the 31%
6-month survival rate observed in the phase II trial of second-line gemcitabine and a similar rate in patients who received gemcitabine under the
IND treatment [9, 10]. The accrual goal for this stratum was 44 eligible
patients. Fourteen or more patients surviving past 6 months would be
considered evidence of the need for further study of this agent. This design
has a significance level of 0.04 and a power of 0.90.
Descriptive factors obtained at baseline in all patients included: (i) prior
surgery, yes or no; (ii) prior radiation therapy, yes or no; (iii) liver metastases, yes or no; and (iv) performance status: 0–1 or 2.
Results
One hundred and sixteen patients were registered on this trial;
61 of whom had received no prior chemotherapy and 55 of
whom had received prior treatment with gemcitabine. Eight
patients were ineligible: five due to missing documentation
and three due to violation of eligibility criteria. Two patients
never received protocol treatment. Overall, 106 patients were
eligible and evaluated for toxicity and efficacy, 58 of whom
were previously untreated and 48 of whom had received
previous chemotherapy.
Patient characteristics
Patient characteristics are summarized in Table 1. The median
age of patients enrolled on this study with and without prior
chemotherapy was 59.0 years (range 38–81 years) and
64.0 years (range 36–80 years), respectively. The majority of
patients were male and Caucasian. Seventy-nine percent of
patients had a performance status of 0 or 1. Eighty-eight percent had liver involvement and 42% had previous surgery.
Efficacy
Previously untreated patients
All 58 previously untreated patients are now off treatment.
The most common reasons for treatment discontinuation were
tumor progression in 40 patients (70%) and toxicity or side-
Table 1. Patient characteristics
Characteristic
No previous chemotherapy (n = 58)
Previous chemotherapy (n = 48)
Median age (range)
64.0 years (36–80 years)
59.0 years (38–81 years)
Male
41 (71%)
29 (60%)
Female
17 (29%)
19 (40%)
46 (79%)
43 (91%)
Gender
Race
White
Black
6 (10%)
3 (6%)
Hispanic
2 (3%)
2 (4%)
4 (7%)
0 (0%)
0–1
47 (81%)
37 (77%)
2
11 (19%)
11 (23%)
Yes
51 (88%)
42 (88%)
No
7 (12%)
6 (12%)
Yes
23 (40%)
21 (44%)
No
34 (60%)
27 (56%)
Asian/Pacific islander
Performance status
a
Liver metastases
Prior surgeryb
a
Southwest Oncology performance status.
Including pancreaticoduodenectomy or palliative choledocojejunostomy with or without gastrojejunal bypass.
b
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Figure 1. Kaplan–Meier survival curves for chemotherapy-naïve (solid line) and previously treated (dashed line) patients with advanced pancreatic
cancer, treated with 5-fluorouracil and eniluracil.
effects in six (11%). The 6-month survival rate for patients
who received oral 5-FU + eniluracil as first-line treatment for
metastatic pancreatic cancer was 34% [95% confidence interval (CI) 22% to 47%] (Figure 1). The 1-year survival rate was
16% (95% CI 6% to 25%). Median survival was 3.6 months.
In the 51 patients with measurable disease, one patient (2%)
had a complete response and three patients (6%) had confirmed partial responses.
Previously treated patients
Of the 48 previously treated patients, one remains on treatment. The most common reason for discontinuation of
treatment was tumor progression in 29 patients (62%). The
6-month survival rate for patients who received oral 5-FU +
eniluracil as second-line therapy was 29% (95% CI 16% to
42%) (Figure 1). The 1-year survival rate for this group of
patients was 10% (95% CI 6% to 15%). Median survival was
3.4 months. All 48 patients had measurable disease. One
patient (2%) had a confirmed partial response. One additional
patient had an unconfirmed response.
Grade 3–4 neutropenia occurred in 19 out of 58 (33%) previously untreated patients and 12 out of 48 (25%) previously
treated patients. Neutropenic fever was rare and occurred in
three (5%) and two (4%) patients, respectively. There was one
case of fatal neutropenic infection in each treatment arm.
Grade 3 or worse diarrhea occurred in six out of 58 (10%)
previously untreated patients and in eight out of 48 (17%) previously treated patients. One patient who received oral 5-FU +
eniluracil as second-line therapy died of dehydration caused
by treatment-related diarrhea. Grade 3 nausea was observed in
nine out of 58 (16%) previously untreated patients and in two
out of 48 (4%) previously treated patients. Grade 3–4 vomiting occurred in seven out of 58 (12%) and one out of 48 (2%)
patients, respectively. Although not a prospective end point of
the study, it appears that previously treated patients tolerated
therapy as well as previously untreated patients. Grade 3 or
worse toxicity occurred in 41 out of 58 (71%) previously
untreated patients and 31 out of 48 (65%) previously treated
patients.
Discussion
Toxicity
The most common toxicities experienced by patients treated
with oral 5-FU + eniluracil are listed in Table 2. Anemia was
the single most common toxicity, with 40 out of 58 (69%) previously untreated patients and 38 out of 48 (79%) previously
treated patients experiencing anemia while on study. However, many of these patients had pre-existing anemia. Grade 3
or worse anemia occurred in only four patients (4%) overall
and all of these patients had received prior chemotherapy.
For the past 5 years, new treatment strategies for patients
with advanced stage pancreatic cancer have focused on optimization of gemcitabine-based treatment. This interest was
prompted by the demonstration that first-line treatment with
gemcitabine was superior to bolus weekly i.v. 5-FU in terms
of both survival and reduction of tumor-related symptoms in
patients with advanced stage disease [3]. Although singleagent 5-FU was found to be therapeutically inferior to gemcitabine in that phase III trial, this should not be interpreted as
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Table 2. Toxicities
Toxicity
First-line therapy (n = 58) grade
Second-line therapy (n = 48) grade
U
0
1
2
3
5
U
0
1
2
4
5
Anemia
0
18
28
12
0
4
0
0
0
10
20
14
3
4
0
0
Neutropenia
0
34
0
5
8
11
0
0
31
4
1
5
7
0
Thrombocytopenia
0
44
6
6
2
0
0
0
36
7
3
1
1
0
Abdominal pain
2
50
2
3
1
0
0
3
29
4
6
5
1
0
Diarrhea
1
38
10
3
6
0
0
0
25
7
8
5
2
1
Fatigue
1
35
12
8
2
0
0
0
25
8
5
10
0
0
Infection with grade 3–4 neutropenia
0
–
–
–
1
1
1
0
–
–
–
1
0
1
Nausea
1
23
16
9
9
–
–
0
22
17
7
2
–
–
Stomatitis
1
42
9
5
1
0
0
0
34
6
5
2
0
1
Vomiting
1
33
14
3
6
1
0
1
37
5
4
1
0
0
U, unknown.
meaning that 5-FU lacks utility in this disease. Median
survival is 5 months for patients treated with single-agent
5-FU, and 5–6 months for patients treated with 5-FU-based
combination regimens in phase III clinical trials [11]. More
recently, at least five phase II trials have evaluated the combination of gemcitabine with 5-FU (± leucovorin) as first-line
therapy in patients with advanced pancreatic cancer [12–16].
Objective response rates ranged from 4% to 22%, median
survival ranged from 4.4–11 months, and 1-year survival rates
ranged from ∼10% to 40%. In a recently reported phase III
trial, Berlin and colleagues compared single agent 5-FU with
the combination of 5-FU + gemcitabine [17]. This trial demonstrated a 1.3 month difference in median survival (6.7 compared with 5.4 months) in favor of the two-drug combination,
a difference that approached, but did not reach, statistical
significance (P = 0.09). These results suggest that there may
be incomplete clinical cross-resistance between 5-FU and
gemcitabine, and that 5-FU has activity that may be complementary to that of gemcitabine.
DPD reduces 5-FU to 5-fluoro-5,6-dihydrouracil (5-FUH2)
[4]. In preclinical studies, eniluracil inactivated >99% of
hepatic DPD activity, thereby blocking the formation of this
and other metabolites, such as α-fluoro-β-alanine (FBAL),
which may interfere with the antitumor activity of 5-FU [4, 20].
Indeed, in preclinical models, eniluracil increased the therapeutic index of 5-FU from <1.0 to 6.0, enhanced the oral bioavailability of 5-FU to 100%, and improved its antitumor
activity [4, 5]. In phase I clinical studies, eniluracil itself
had no appreciable toxicities, but significantly increased the
plasma half-life of 5-FU from 15 min to 5 h and reduced 5-FU
clearance by 18-fold [18]. The plasma concentration–time
curve (AUC) for an oral dose of 5-FU of 20 mg/m2 that was
preceded by eniluracil approximated that of a 600 mg/m2 dose
of 5-FU administered intravenously without eniluracil [18].
Partial responses were observed in several patients with
advanced colorectal cancer that had progressed on intraven-
ous 5-FU + leucovorin [18]. Taken together, the preclinical,
pharmacological and clinical data on eniluracil + oral 5-FU
was sufficiently intriguing to warrant evaluation of this
combination in patients with advanced pancreatic cancer.
Our study evaluated eniluracil, administered on days 1–7, in
combination with oral 5-FU, administered on days 2–6, in
patients with metastatic pancreatic cancer. Patients were
drawn from two populations: those who were previously
untreated for metastatic pancreatic cancer, and those who had
received gemcitabine as initial treatment for metastatic disease
and experienced disease progression. Because the beneficial
effects of therapy for patients with adenocarcinoma of the
pancreas may not be accurately reflected by tumor shrinkage
(i.e. response rate), the primary end point selected for this trial
was survival. Expectations for this therapy were influenced by
clinical experience with gemcitabine. As first-line treatment
in patients with locally advanced or metastatic pancreatic
cancer, gemcitabine is associated with a median survival of
5.1–6.3 months and a 6-month survival rate of 46–52% [3, 10,
19, 20]. The phase II study and IND treatment experience with
gemcitabine as second-line therapy in patients with advanced
pancreatic cancer reported median survivals of 3.9–4.4 months
and 6-month survival rates of ∼31% [9, 10]. The parameters of
this study were set such that the combination of oral 5-FU +
eniluracil would be pursued further if the 6-month survival
rate was consistent with a true rate in excess of 55% when used
in the front-line setting, and 40% when used in the second-line
setting. Neither goal was achieved. Oral 5-FU + eniluracil was
associated with a 6-month survival rate of 34% (95% CI 22%
to 47%) when used as first-line chemotherapy, and 29% (95%
CI 16% to 42%) when used as second-line chemotherapy.
Although prospective evaluation of the impact of this therapy
on tumor-related symptoms was not performed due to the
exploratory nature of this study, it is notable that 68% of
patients treated with oral 5-FU and eniluracil experienced a
grade 3 or worse adverse event while on study. It should be
1581
noted that some of the serious adverse events were more likely
to be related to the effects of progressive pancreatic cancer
than to the effects of the chemotherapy. Nevertheless, the
combination of 6-month survival rates that fall below the
lower limits of interest and the high frequency of grade 3 or
worse adverse events suggest that the combination of day 2–6
oral 5-FU + day 1–7 eniluracil does not warrant further
evaluation in patients with metastatic adenocarcinoma of the
pancreas.
There are several possible explanations for these results.
The first is that the addition of eniluracil was not sufficient to
enhance the limited clinical activity of 5-FU. Recent clinical
trials in patients with advanced colorectal cancer suggest that
this is the most likely explanation. Promising activity was
observed with this regimen (with or without leucovorin) in
phase II trials, including partial response rates of 21–25% and
median survival of 13.6 months in patients with previously
untreated metastatic colorectal cancer [21, 22]. However,
none of the 25 patients previously treated with intravenous
5-FU and leucovorin responded to the combination of oral
5-FU + eniluracil, suggesting a high degree of clinical crossresistance between the two therapies. In addition, preliminary
results from two phase III trials indicate that oral 5-FU +
eniluracil is no better, and may indeed be inferior to intravenous 5-FU + leucovorin in patients with previously
untreated metastatic colorectal cancer.
Another possible explanation is that patient selection may
have influenced our results as much as, if not more than, the
treatment. Most clinical trials in the advanced pancreatic
cancer setting include a mixture of stage II, III and IV patients.
Our survival estimates were based on figures derived from
those studies. Stage of disease is a consistent and strong prognostic indicator for survival in patients with pancreatic
cancer [10]. Our study required patients to have metastatic
disease at the time of enrolment. In the IND treatment experience with gemcitabine, for instance, the median survival for
patients with stage IV disease was only 4.4 months [8].
However, even taking this into account, the 3.6-month median
survival observed for previously untreated patients who
received oral 5-FU + eniluracil in the current trial falls short of
this threshold.
A third possible explanation is that the dose and/or schedule
of therapy was suboptimal. In fact, a phase II study of the
5-day regimen of oral 5-FU and the 7-day regimen of
eniluracil in patients with metastatic colorectal cancer used a
25 mg/m2/day dose of 5-FU rather than the 20 mg/m2/day dose
used in this study [21]. However, this dose was not tolerated as
six of the first 20 patients treated in that trial were hospitalized
with grade 4 neutropenia and sepsis [21]. A 28-day-on/7-dayoff treatment schedule has also been evaluated in patients with
metastatic colorectal cancer [22]. The 25% objective response
rate and 5.2-month progression-free survival observed for
this schedule was very similar to the 21% response rate and
4.4-month progression-free survival observed using the 5-day
schedule [22]. This same 28-day-on/7-day-off treatment has
been evaluated in patients with advanced pancreatic cancer,
and preliminary results reported good tolerability and objective responses in three out of 41 (7.3%) patients [23]. Survival
data, however, are not available for that study.
There are several possible explanations for the high rate of
grade 3 or 4 adverse events observed in this trial. The first is
that patients with pancreatic cancer represent a relatively frail
patient population and, as such, are more prone to toxicities
than patients enrolled in phase I trials. The second is that there
is evidence that the recommended dose of 25 mg/m2/day from
phase I studies was not well tolerated in phase II. In one study,
six of the first 20 patients with colorectal cancer treated with
this dose required hospitalization for neutropenia and sepsis
[21]. A third is that we chose to use the term ‘adverse events’
rather than ‘toxicities’ to reflect the fact that, in some cases,
these events may have been due to factors other than the drug,
such as tumor-related symptoms, side-effects of other medications or intercurrent illnesses.
In summary, the combination of oral 5-FU + eniluracil does
not demonstrate sufficient clinical activity, as reflected by
6-month survival rate, to warrant further study as first- or
second-line therapy in patients with metastatic adenocarcinoma of the pancreas. In addition, the high frequency of grade 3
or worse adverse events makes it unlikely that this regimen
could be safely combined with other drugs for the treatment of
patients with advanced pancreatic cancer.
Acknowledgements
This investigation was supported in part by the following
Public Health Service Cooperative Agreement grants,
awarded by the National Cancer Institute, Department of
Health and Human Services: CA38926, CA32102, CA45450,
CA35176, CA35261, CA46441, CA67663, CA-22433, CA12644, CA35281, CA58415, CA58416, CA58882, CA52386,
CA35192, CA37981, CA35431, CA20319, CA45461, CA58723, CA35119, CA58861, CA76448, CA45807, CA63844,
CA42777, CA45377, CA35178, CA12213, CA-45560, CA63850, CA35128, CA14028, CA04919, and an unrestricted
grant from GlaxoSmithKline (Collegeville, PA, USA).
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