Until recently, strategies aimed at modulating
5-fluorouracil (5-FU) have focused on 5-FU activation pathways.
However, the recent recognition of the clinical importance of
dihydropyrimidine dehydrogenase (DPD)the first enzyme in a
degradative pathway that rapidly catabolizes more than 80% of
systemically administered 5-FUhas led to new potentials for
improving the efficacy and safety of 5-FU. The limited antitumor
activity of 5-FU may be due in part to its pharmacokinetic
characteristics, which are dependent on DPD and have been well
described. It has also been reported that intratumoral DPD
expression is an independent determinant of tumor response to
Eniluracil (776C85, 5-ethynyluracil) is a potent inactivator of
DPD. The chemical structure of eniluracil in comparison with that
of 5-FU is shown in Figure 1.
In preclinical studies, doses of eniluracil sufficient to inactivate
more than 99% of endogenous DPD were nontoxic and exhibited no
antiproliferative activity. In animal models, pretreatment with
eniluracil significantly increased the bioavailability and reduced
the pharmacokinetic variability of oral 5-FU. In three rodent tumor
models, eniluracil also increased the antitumor efficacy of 5-FU and
increased the therapeutic index of 5-FU by up to sixfold.[5,6]
Preclinical evidence suggests that eniluracil may improve the
efficacy of 5-FU by preventing the formation of 5-FU catabolites that
may impair antitumor activity and increase 5-FU toxicity. It was
also demonstrated in vitro that DPD activity was an independent
factor significantly related to 5-FU sensitivity and that eniluracil
enhanced 5-FU cytotoxicity in six cell lines expressing high basal
DPD activity. By inhibiting DPD, eniluracil may eliminate one
potential mechanism for 5-FU chemoresistance.
Eniluracil is currently in phase III clinical development. Baker et
al reported that the oral bioavailability of 5-FU is excellent and is
approximately 100% in the presence of eniluracil at a dose of 3.7
mg/m². This study paved the way for the development of two
completely oral 5-FU regimens, which are currently under clinical
investigation: The first regimen involves a chronic dosing schedule
in which eniluracil and 5-FU are administered orally BID in a 10:1
ratio for 28 days of a 5-week course. The 5-FU dose is 1.0 or 1.15
mg/m². In the second regimen, eniluracil is given orally once
daily on days 1 through 7 and 5-FU given orally once daily on days 2
through 6. Results of the initial phase I trial for this schedule
showed that it was well tolerated and demonstrated antitumor activity.
The phase II/III development of eniluracil has focused on three
important tumor types: colorectal cancer, breast cancer, and
Because 5-FU-based chemotherapy has been the mainstay of therapy for
advanced gastrointestinal and upper aerodigestive cancers, colorectal
cancer was an obvious choice for phase II development of eniluracil.
Mani et al recently reported preliminary results of a multicenter
phase II trial evaluating the chronic dosing regimen of
eniluracil/5-FU in patients with previously untreated metastatic
colorectal cancer (Table 1).
Eligible patients had measurable lesions and had received no
previous chemotherapy or only adjuvant chemotherapy completed at
least 12 months prior to study entry. A Karnofsky performance status (KPS) ³
70 and adequate organ function were also required. After 28 patients
were treated with 5-FU 1.0 mg/m² BID, the protocol was amended
to increase the 5-FU dose to 1.15 mg/m² because of the minimal
toxicity observed at the lower dose. The response rates were 25% and
29% for the 1.0 and 1.15 mg/m² dose groups, respectively. In
addition, there appeared to be a higher percentage of stable disease
for the higher-dose group compared with the lower- dose group (57% vs
36%). These promising results compare favorably to those reported
with regimens of intravenous 5-FU and leucovorin.[12,13]
These preliminary results prompted randomized phase III comparative
trials in previously untreated patients with metastatic colorectal
cancer. Currently, two large multicenter phase III studies are under
way. In the United States, a phase III trial (FUMA3008) is comparing
eniluracil/5-FU given on the chronic 28-day schedule vs a commonly
used 5-day intravenous regimen of leucovorin 20 mg/m²/day and
5-FU 425 mg/m²/day. The sample size is approximately 900
patients and the primary end point is survival. A similar trial
(FUMB3002) is under way in Europe. It has the same two treatment arms
as the US trial but the sample size is approximately 500 patients and
the primary end point is response rate. Survival is a secondary end
point. Both trials will also evaluate progression-free survival and
quality of life. Enrollment in these trials is expected to be
completed by early 1999.
The combination of eniluracil/5-FU is also being evaluated as a
treatment for advanced breast cancer. An overall response rate of 29%
was reported in a series of small phase II studies of continuous
intravenous 5-FU in heavily pretreated advanced breast cancer
patients. Based on these results, exploratory phase II trials in
previously treated breast cancer patients were initiated. In the
United States, patients with metastatic breast cancer who are
resistant to or not candidates for further treatment with
anthracyclines and taxanes are currently being enrolled in two
multicenter phase II trials of eniluracil/5-FU. Preliminary results
from one of these trials were recently reported by Rivera et al.
Of 31 evaluable patients, 5 had partial responses for a response rate
of 16%. Additional phase II/III studies are planned, as are phase I
studies of eniluracil combined with commonly used chemotherapy agents
such as paclitaxel, docetaxel, and vinorelbine.
Although continuous intravenous 5-FU has not been widely used for the
treatment of metastatic pancreatic cancer, Hansen et al reported on
16 patients with metastatic pancreatic cancer who received continuous
infusion 5-FU (200-300 mg/m²/day). In a disease in which
objective responses are rare, three partial responses were observed,
for an overall response rate of 19%. An additional eight patients had
stable disease, with a median duration of disease stabilization of 5
months (range, 3 to 10 months). As a result of these preliminary
findings and the lack of effective therapy for this
difficult-to-treat tumor, phase II and phase III trials of
eniluracil/5-FU were started simultaneously. The non-controlled
multicenter phase II trial in previously untreated patients with
advanced pancreatic cancer was conducted in Europe and has completed
accrual. Results have not yet been reported. In the United States, a
large phase III trial is comparing eniluracil/5-FU given on the
chronic 28-day schedule vs gemcitabine, a recently approved agent for
this disease. Accrual is nearly complete, and results are expected in 1999.
Preliminary results of studies of eniluracil suggest that this agent
produces antitumor efficacy with a low incidence of severe
toxicities. A preliminary safety analysis for the chronic 28-day
dosing regimen, involving data from 108 patients treated in three
different studies, was recently conducted (see Table
2). The three studies included in the analysis are FUMA1003
(phase I dose-escalation trial for the 28-day dose regimen), FUMA2003
(phase II breast cancer trial reported by Rivera et al), and
FUMA2006 (phase II colorectal cancer trial reported by Mani et al).
Table 3 lists the most frequently occurring nonhematologic
toxicities for the 28-day regimen of eniluracil/5-FU, most of which
are gastrointestinal in nature. Severe (grade 3 and 4) diarrhea
occurred in fewer than 10% of patients and completely resolved with
treatment discontinuation. After cessation of diarrhea, patients
could usually resume therapy. In contrast, up to 27% of patients
treated with the common 5-day regimen of 5-FU and leucovorin may
experience severe diarrhea. Severe nausea and vomiting occurred in 5%
and 2% of patients, respectively.
Hand-foot syndrome, also known as palmar-plantar erythrodysaesthesia,
is observed in 24% of patients who receive continuous-infusion
5-FU. While the causative mechanism for this toxicity is unknown,
it usually resolves with discontinuation of treatment. Fewer than 5%
of patients have experienced this adverse reaction when treated with
the chronic 28-day dosing schedule of eniluracil/5-FU. The relative
lack of hand-foot syndrome is clearly a potential advantage for the
The hematologic toxicity of the eniluracil/5-FU combination is
summarized in Table 4. Grade 4
granulocytopenia occurred in 1% of patients. Severe thrombocytopenia
requiring platelet transfusion was rare. The incidence of marked
myelosuppression with the chronic 28-day regimen was low, pointing to
the observation that diarrhea usually occurs in the absence of marked
myelosuppression. The relative lack of concomitant diarrhea and
granulocytopenia lowers the risk of sepsis or morbidity that would
require hospitalization, as occurs in some patients treated with
intravenous regimens of 5-FU/leucovorin.
The toxicity profile for eniluracil/5-FU is similar for patients with
different types of cancer. However, breast cancer patients appear to
have a higher incidence of granulocytopenia than colorectal cancer
patients: Granulocytopenia ³ grade 2
occured in 14% and 5.5% of patients with breast cancer and colorectal
cancer, respectively. This difference is probably related more to the
effects of previous chemotherapy than to the tumor type itself,
because all breast cancer patients had previously received
anthracyclines and taxanes, whereas those with colorectal cancer had
not received any previous chemotherapy for metastatic disease.
Interestingly, the incidence of diarrhea ³
grade 2 was higher in the colorectal cancer population than in the
breast cancer population (25% vs 14%); this difference may be related
to previous surgical procedures but a disease effect cannot be ruled
out. No hand-foot syndrome was observed in the two phase II studies
involving breast and colorectal cancer patients.
The effect of dose on toxicity was also evaluated. Table
5 lists common toxicities according to initial 5-FU dose (ie,
1.0 or 1.15 mg/m²). The incidences of ³
grade 2 diarrhea, nausea, vomiting and granulocytopenia were similar
in the two dose groups, which supports the hypothesis (based on
preclinical data) that eniluracil increases the therapeutic index of 5-FU.
Other adverse experiences that have been reported include cholestatic
jaundice, deep vein thrombosis, and nystagmus. The first two events
may be related to metastatic cancer, but a relationship to
eniluracil/5-FU cannot be eliminated because the patients were
receiving treatment at the time of the event. Nystagmus has been
observed previously in patients receiving 5-FU-based chemotherapy.
In summary, eniluracil is a promising new agent with a novel
mechanism of 5-FU modulation. Extensive phase II/III trials in
patients with colorectal, breast, and pancreatic cancers as well as
other solid tumors are ongoing. Preliminary results of a phase II
study in colorectal cancer are encouraging. The chronic 28-day
regimen is well tolerated with a relatively low incidence of severe
toxicities (in particular, hand-foot syndrome) as compared with that
of standard 5-FU-based regimens. The combination of eniluracil/5-FU
may prove to be a convenient, well tolerated and effective
alternative to intravenous 5-FU-based chemotherapy regimens.
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