(2-deoxy-2,2-difluorocytidine) is a new antimetabolite being
increasingly used in the treatment of solid tumors. It is an analog
of deoxycytidine and cytosine arabinoside (Ara-C) (Figure
1) that has shown significant activity as a single agent in
lung, breast, pancreas, and ovarian cancers. Gemcitabine (dFdC) is
activated by deoxycytidine kinase to dFdC-5¢-monophosphate
(dFdCMP). The latter is further metabolized to dFdC-5¢-diphosphate
(dFdCDP) and dFdC-5¢-triphosphate
(dFdCTP), which, when incorporated into deoxyribonucleic acid (DNA),
results in masked chain termination (Figure
2). In comparison to Ara-C triphosphate (Ara-CTP) incorporation
into DNA, dFdCTP is less readily excised from DNA by DNA exonuclease.
Thus, dFdCTP accumulates intracellularly to a greater degree than
Ara-CTP, which may account, at least in part, for its different
spectrum of preclinical and clinical activity. In addition, dFdCDP
blocks DNA synthesis by another mechanism, which is the inhibition of
It is now well recognized that the activity of gemcitabine is very
schedule-dependent. Preclinical testing demonstrated an excellent
broad spectrum of antitumor activity in animals carrying human tumor xenografts.
Although the initial phase I trials determined the maximum tolerated
dose of gemcitabine to be 800 to 1,000 mg/m²when patients were
dosed once a week for 3 of every 4 weeks, subsequent phase II trials
found this dose to exhibit minimal toxicity. The safety profile of
gemcitabine was unusually mild for such an active agent in solid
tumors. Hematologic toxicity was mild and short-lived with modest
World Health Organization (WHO) grades 3 and 4 for hemoglobin (6.4%
and 0.9% of patients, respectively), leukocytes (8.1% and 0.5%),
neutrophils (18.7% and 5.7%), and platelets (6.4% and 0.9%). The
incidence of grades 3 and 4 infection associated with this level of
myelosuppression was low (0.9% and 0.2%). Transaminase elevations
occurred frequently, but they were usually mild and rarely
dose-limiting. Nausea and vomiting were mild, rarely dose-limiting,
and generally well controlled with standard antiemetics. Flulike
symptoms were experienced in a small proportion of patients but were
of short duration. In cases where edema/peripheral edema were
experienced, there was no evidence of any association with cardiac,
hepatic, or renal failure. Hair loss was rare, with WHO grade 3
alopecia reported in 0.5% of patients. Furthermore, gemcitabine
displayed minimal toxicity in elderly patients, and the side-effect
profile does not seem to be affected by patient age.
Abbruzzese reviewed the extensive data generated in phase I
studies with gemcitabine. These studies demonstrated important
schedule-dependent differdifferences in toxicity profile and activity
of gemcitabine. Frequent drug administration produced a high
incidence of toxicities: in the daily schedule, flulike symptoms
(fever, malaise, and headache) were experienced, and in some
patients, idiosyncratic episodes of severe hypotension; in the
twice-a-week schedule, the dose-limiting toxicity was
thrombocytopenia. Less-frequent drug administration was better
tolerated (myelosuppression was the dose-limiting toxicity), but
little efficacy was observed.
The first objective of this phase I study was to determine the
toxicity profile and the maximum tolerated dose of the combination of
gemcitabine and UFT (uracil and tegafur in a 4:1 molar ratio) plus
oral calcium folinate (Orzel) in patients with advanced cancers. The
second objective was to measure the rate of objective tumor response,
duration of response, and overall survival in patients treated with
the combination of gemcitabine and UFT plus oral calcium folinate.
The rationale for combining gemcitabine with UFT plus oral calcium
folinate is their nonoverlapping toxicities: the dose-limiting
toxicity of gemcitabine is hematologic, whereas nonhematologic
toxicity is the major dose-limiting toxicity of UFT plus oral calcium folinate.
The Human Investigational Committee approved the study at Wayne State
University, and patients provided signed, written informed consent.
Patients must have histologic or cytologic proof of advanced
malignancy and disease evaluable for response. Life expectancy should
be greater than 3 months, and patients must have a performance status
of 0 to 2 on the Southwest Oncology Group scale. Serum creatinine
concentration must be £ 1.5 mg/dL.
Patients must have hemoglobin ³ 8.0
g/dL, absolute neutrophil count ³
1,500/µL, platelet count ³
100,000/µL, and total serum bilirubin £
2.0 mg/dL. Serum aspartate aminotransferase concentration must be
less than 3.0 times the upper range of normal, provided patients have
evidence of hepatic metastases.
Dose escalations of gemcitabine and UFT plus oral calcium folinate
will be according to the schema outlined in Table
1. At least three patients will be entered at each dose level
until reaching the maximum tolerated dose. The 90-mg/day calcium
folinate dose will be kept constant throughout the study. Dose
escalations are not allowed within the same patient. A minimum of six
patients will be entered at a given dose level if one or more of the
initial three patients at that dose level develop 1) grades 3/4
nonhematologic toxicity (excluding alopecia), 2) grade 4
thrombocytopenia, 3) grade 4 neutropenia complicated with either
fever or treatment delays of > 1 week, or 4) dose withholding
during a treatment cycle (except for diarrhea).
Drugs and Treatment
Gemcitabine will be administered intravenously over 30 minutes on
days 1, 8, and 15 of a cycle; cycles will be repeated every 28 days.
UFT plus oral calcium folinate will be administered orally in three
divided doses. The dose of UFT will be escalated in successive
cohorts of patients, whereas the dose of calcium folinate will remain
constant at 90 mg/day. The dose of UFT per day is calculated on the
basis of the body surface area and rounded off to the nearest 100 mg.
Immediately before a dose of UFT, 30 mg of calcium folinate will be
administered orally. UFT plus oral calcium folinate will be
administered on days 1 to 21 of each cycle. Treatment will be
continued until disease progression or undue toxicity.
Eight patients have been accrued to this study, five of whom were
evaluable for toxicity at the time of preparing this article (Table
2). Table 3 summarizes
the toxicity data. The maximum tolerated dose has not been reached,
based on the follow-up of the five patients reported so far. The
major toxicity is hematologic; nonhematologic toxicity has been
absent at these two dose levels. One patient at dose level 1 has
grade 4 thrombocytopenia but has not required any platelet
transfusions. This patient was previously heavily treated with
several lines of chemotherapy including alkylating agents.
The combination of gemcitabine and UFT plus oral calcium folinate
represents an attempt to modulate 5-fluorouracil (5-FU)
pharmacodynamics in humans. Gemcitabine and UFT are both
antimetabolites that inhibit DNA synthesis by at least two different
mechanisms: DNA chain termination with gemcitabine and inhibition of
thymidylate synthase by 5-fluoro-2¢-deoxyuridylate
(FdUMP). In addition, the metabolite dFdCDP inhibits ribonucleotide
reductase, which is the key enzyme in the generation of
deoxyribonucleotide. Gemcitabine may therefore enhance DNA synthesis
inhibition by its additive effect to UFT, and also by augmenting the
inhibition of thymidylate synthesis and reducing the concentration of
deoxyuridine monophosphate (dUMP), which competes with FdUMP for
Several studies have been initiated to determine the tolerability and
the maximum tolerated dose of gemcitabine when combined with 5-FU.
The combination of gemcitabine and continuous-infusion 5-FU was
investigated and shown to produce neutropenia as its dose-limiting
toxicity. The maximum tolerated dose of the combination was
gemcitabine 900 mg/m²/week (3 of 4 weeks) and 5-FU 200
mg/m²/day. In another study, the dose-limiting toxicity was
nonhematologic when 5-FU 300 mg/m²/day was combined with
low-dose gemcitabine (300 mg/m²/week, 3 of 4 weeks). These
two early reports on the combination of gemcitabine and
continuous-infusion 5-FU indicated that the dose-limiting toxicities
resulting from the combination, whether hematologic or
nonhematologic, depended on the ratio of gemcitabine to 5-FU dose.
The combination of gemcitabine and UFT plus oral calcium folinate may
be further developed in the treatment of cancers that are responsive
to either drug, but particularly in disease where both drugs have
shown notable antitumor activities (eg, breast cancer). The optimum
schedule of administration of gemcitabine and UFT plus oral calcium
folinate will also need further investigation.
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