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Schedule Dependency of 5-Fluorouracil

Schedule Dependency of 5-Fluorouracil

ABSTRACT: 5-Fluorouracil (5-FU) is cell-cycle specific for its cytotoxicity and has a pharmacokinetic profile characterized by a short, single-dose half-life of 10 to 20 minutes in plasma. Efforts to maximize its clinical efficacy have been directed at overcoming this short half-life. Strategies have included prolonging intracellular exposure by biochemical modulation or administration by infusional schedules, and more recently by chronic oral dosing. A number of clinical trials comparing routes of administration and biochemical modulation of 5-FU are presented in this article. Issues of dose intensity, differing toxicity profiles, and pharmacoeconomics are reviewed. [ONCOLOGY 7(Suppl 3):26-32, 1999]


Introduction

Schedule dependency for fluorinated
pyrimidine-based therapy has been an issue since Ansfield’s
early investigations.[1] Until very recently, the pharmacologic
armamentarium against colorectal cancer was extremely limited.
Because single-agent 5-fluorouracil (5-FU) has been the mainstay in
treatment of this disease, much of the clinical study of this drug
has occurred in the setting of colorectal cancer. Consequently,
clinical trials of 5-FU–based regimens for disseminated
colorectal cancer have focused on biochemical modulation and schedule
dependency as a means of enhancing therapeutic efficacy.

5-FU Pharmacokinetics

Mechanism of Action

A major mechanism of 5-FU action is inhibition of thymidylate
synthase activity by competitive binding of F-dUMP (5-fluorodeoxyuridine
monophosphate) with the dUMP binding site on the enzyme molecule,
thus inhibiting the rate-limiting step for thymidine and, therefore,
DNA synthesis. This process is cell-cycle (S-phase) specific, making
drug activity irregular against the sensitive portion of the tumor
cell population. Potential for cytotoxic activity is further impaired
by the rapid catabolic rate for the drug, reflected in the short
plasma half-life of 10 to 20 minutes, when given as a bolus injection.[2,3]

5-FU has also been shown experimentally and in clinical trials to
function as a radiation sensitizer.[4] In this setting, short half-life,
overlapping toxicities, and enhanced toxicity with the addition of
modulators have additional therapeutic implications. Furthermore, in
the disseminated disease setting, where palliation is a goal—in
addition to enhancement of response rates, time-to-progression, and
survival—the issue of type and degree of toxicity is an
important one.

Dose Intensity

To increase tumor cell–kill and response rates in the
disseminated disease setting and to project the best regimen for
eradication of micrometastases in the adjuvant setting, dose
intensity may be important in determining the schedule for optimal
drug delivery. Dose intensity is defined as the amount of drug
delivered per unit of time, typically reported as milligrams per
square meter per week or per 28 days, regardless of the schedule
used.[5] A dose-intense regimen may or may not be associated with
high peak drug levels. Continuous administration of chemotherapeutic
regimens may be quite dose-intensive but may also be associated with
lower peak concentrations.[6] Acceptability of dose-intense regimens
is dependent on the degree of toxicity encountered, which, in turn,
may depend on whether the goal of therapy is palliative or curative.
Drug metabolism and catabolism also need to be taken into account in
the design of dose-intense chemotherapy regimens.

For the standard Mayo daily times 5, once-a-month regimen of 5-FU
plus low-dose calcium folinate being used in both adjuvant and
disseminated settings, a 5-FU dose of 375 to 425 mg /m² yields a
28-day dose of 1,900 to 2,100 mg/m². For the Roswell Park weekly
regimen of 500 mg/m² of 5-FU with high-dose calcium folinate
administered for 6 of 8 weeks in the same settings, a 28-day dose of
1,500 mg/m² is received. For continuous infusions of 5-FU, 200
to 300 mg/m²/day, with or without calcium folinate, the
comparable 28-day dose is 5,600 to 8,400 mg/m², and for the
intermittent, weekly, high-dose 24-hour infusion of 2,600 mg/m²,
the 28-day dose is 10,400 mg/m². These doses are contingent on
no dose reduction, so the additional question is raised of what
relative percentage of patients receiving each regimen will
experience a degree of toxicity requiring dose reduction.

In the face of an obvious dose-intensity advantage conferred by the
infusional regimens, it is noteworthy that we fail to see comparable
differences in activity. Is the explanation that there is a maximum
dose intensity of 5-FU beyond which no further clinical activity is
achieved? Dose intensity is based on area under the
concentration-time curve for plasma pharmacokinetics. As such, is the
constant level of drug for diffusion into the cell, which
characterizes the infusional regimens, balanced by ternary complex
formation and degree of intracellular polyglutamylation of bolus
regimens administered with calcium folinate? Or, do other factors,
such as intratumor levels of thymidylate synthase or mutations of
oncogenes and tumor suppressor genes, ultimately override both dose
intensity and biochemical modulation in determination of response?

Biochemical Modulation

The value of altering the schedule of or biochemically modulating
5-FU was tested in phase I and II trials designed to identify
intravenous and oral doses of calcium folinate for addition to
continuous infusion 5-FU.[7,8] Toxicities
encountered—predominantly plantar-palmar erythrodysesthesia
(hand-foot syndrome) and stomatitis—were of higher grade and
earlier onset than those that occurred with single-agent 5-FU,
resulting in a net reduction in dose intensity of 5-FU. The question
remained, however, about the relative roles of biochemical modulation
vs schedule dependency. To answer this question, the Southwest
Oncology Group (SWOG) [9] conducted a phase II trial in which more
than 600 patients were randomized over a 3-year period to paired
regimens of bolus (daily times 5, once a month; weekly) and
infusional (protracted low-dose; weekly high-dose) 5-FU, with and
without biochemical modulators (calcium folinate, PALA [N-phosphoroacetyl-L-aspartic
acid]). None of the regimens tested demonstrated a statistical
superiority for either response or survival. Response rates ranged
from 15% to 29%; median survival ranged from 11 to 15 months.

In a subsequent phase III trial conducted by the Eastern Cooperative
Oncology Group (ECOG), investigators randomly assigned more than
1,100 patients to five treatment arms of 5-FU given by weekly bolus
or weekly infusion, with or without modulation (intravenous or oral
calcium folinate, PALA, or a-interferon).[10] Again, no regimen
demonstrated statistically superior activity over the others. Median
survival was nearly identical to that in the Southwest Oncology Group
trial, ranging from 13 to 15 months.

Toxicity

In both of these trials, the infusion arms demonstrated a lower
percentage of grades 3 and 4 toxicity. Furthermore, the pattern of
dominant toxicities—ie, stomatitis and hand-foot
syndrome—allows for earlier intervention with careful patient
observation, thus avoiding higher toxicity grades with consequent
extensive dose reduction. Given the inherent increased dose and the
less frequent dose reduction encountered, the dose-intensity
advantage persists for these arms. Though not reaching statistical
significance, in the SWOG trial a trend toward response and survival
benefit was seen for the single-agent 5-FU infusion arms (Figure
1
, Figure 2, and Figure
3
).

Meta-Analysis

The Meta-Analysis Group in Cancer examined data from seven
international randomized trials that included com-

parable bolus and infusion regimens, with or without calcium folinate
modulation.[11] Pooled data demonstrated a statistically significant
response advantage for continuous-infusion 5-FU compared with bolus
5-FU (Table 1). A small
survival advantage was also detected for the infusion treatment (Table
2
). Differences were less obvious when both methods of 5-FU
administration were modulated by calcium folinate. As expected,
toxicity patterns differed between bolus and infusion regimens.

Cost Comparisons

In addition to response, survival, and toxicity analyses, the issue
of comparative costs has become important in today’s
increasingly controlled medical market. A major component of cost
differential between these two modes of drug administration is the
up-front cost of catheter placement. When amortized over the course
of treatment, this cost, along with pump rental charges, tends to
lessen the cost differences over time, particularly for those
patients who respond to therapy. The expense of calcium folinate used
with the bolus regimens may also serve to offset differences when
compared with single-agent infusion regimens.[12,13]

Treatment of toxicity related to the different therapeutic regimens
also needs to be included in this analysis: hospitalization for
dehydration and neutropenic sepsis is more commonly required for
calcium folinate–modulated bolus 5-FU schedules, whereas the
expense of treating catheter infections and thromboses needs to be
figured into the analyses for infusional regimens. These analyses are
difficult to accurately perform, as regional differences in the cost
of medical services also enter the equation. The Meta-Analysis Group
in Cancer is currently undertaking this task for the patients
included in the report cited above.

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