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The Role of UFT in Combined- Modality Therapy

The Role of UFT in Combined- Modality Therapy

ABSTRACT: Fluorinated pyrimidines have long been used as radiosensitizers in combined-modality therapy for solid tumors. Nonetheless, the most commonly used drug, 5-fluorouracil (5-FU), is inconvenient to administer, particularly when given by continuous intravenous infusion. Continuous infusion 5-FU does offer a survival advantage over bolus in the treatment of large bowel tumors. This holds true regardless of whether radiation therapy is concomitantly given. UFT, a combination of uracil and tegafur (in a molar ratio of 4:1), is an attractive alternative. Trials to date suggest at least chemotherapeutic equivalence compared to 5-fluorouracil, and UFT is much simpler to administer. UFT is administered orally and can safely be combined with oral leucovorin. There is profound scientific rationale for using UFT with radiation therapy, and early trials in gastrointestinal malignancies demonstrate the safety and efficacy of the combination. Further studies will determine the optimal timing and uses for concomitant UFT and radiation therapy. [ONCOLOGY 13(Suppl 5):47-54, 1999]


Introduction

The use of concomitant chemoradiotherapy has a
strong theoretical and practical rationale, and combined-modality
treatment has proven effective for a variety of human solid
malignancies. Multiple prospective randomized trials have
demonstrated improved local control and survival for patients with
locally advanced, nonmetastatic gastrointestinal malignancies treated
with 5-fluorouracil (5-FU)–based chemoradiotherapy, compared to
5-FU or radiation therapy alone. While the mechanism(s) for the
interaction has not been precisely defined, chemotherapy may increase
the activity of radiation therapy through direct and selective
eradication of radioresistant cells or through a cellular interaction
with radiation therapy, leading to inhibition of structural repair
and resulting in decreased radioresistance.

5-FU appears to be a more effective radiosensitizer when given by
continuous intravenous infusion; however, that mode of administration
is cumbersome. Uracil and tegafur (in a molar ratio of 4:1 [UFT]), an
oral 5-FU prodrug, behaves pharmacologically like continuous
intravenous infusion 5-FU and is a logical choice for combination
with radiation therapy. This article reviews the structure and
activity of both 5-FU and UFT, the use of fluoropyrimidines with
radiation therapy, and ongoing trials of UFT as a component in
combined-modality therapy.

5-Fluorouracil

5-FU has been a mainstay in the solid tumor chemotherapy
armamentarium for more than 40 years. During this time, numerous
attempts to bolster its effectiveness have been made, both by
changing the route of administration and through modulation by
codelivery with other agents. Despite these attempts, reported
response rates remain low, and administration remains burdensome,
requiring intravenous access and multiple patient clinic visits per cycle.

5-FU is a rationally designed compound synthesized by Heidelberger
several decades ago.[1] It belongs to the antimetabolite class of
antineoplastics and is a pyrimidine antagonist that resembles uracil,
substituting fluorine for hydrogen at position 5 (Figure
1
). At least three major mechanisms of action have been
postulated for 5-FU, all involving activation by metabolism to
various nucleotides.[2,3] 5-FU is converted to 5-fluoro-2¢deoxyuridine
(FUdR) by thymidine phosphorylase. FUdR is then further
phosphorylated by thymidine kinase to 5-fluoro-2¢deoxyuridine
monophosphate (FdUMP). FdUMP forms a stable covalent compound with
thymidylate synthase, leading to the inhibition of that enzyme with
subsequently decreased de novo synthesis of thymidine monophosphate
(dTMP). This ultimately results in substandard DNA synthesis and repair.

A controversial proposed mechanism of action involves 5-FU
incorporation through fluorodeoxyuridine triphosphate (FdUTP) into
DNA. DNA synthesized in the presence of 5-FU has a markedly smaller
strand size and is more prone to strand breaks. This fragility may
result from the actual excision of 5-FU from the DNA or may be
related to inefficient repair of normally occurring trauma. However,
the extent to which this incorporation is related to cytotoxicity,
particularly the magnitude of the effect from thymidylate synthase
inhibition, continues to be debated.

Finally, 5-FU is somewhat unique in that it is extensively
incorporated through fluorouridine triphosphate (FUTP) into all
classes of RNA, where it leads to misprocessing and/or
misfunction.[4] This clearly correlates with cytotoxicity in various
solid tumor cell lines.

5-FU is not convenient to administer. Oral bioavailability varies
from 28% to 100%.[3] Conventional IV bolus dosing leads to short
periods (less than a few hours) during which plasma concentrations
are above the putative cytotoxic level. Thymidylate synthase
inhibition in particular is S-phase dependent, so the 6- to 20-minute
half-life following bolus administration does not seem to overlap
cell division for most of a bulky solid tumor and should not be the
major mechanism of action for bolus 5-FU.[5]

Continuous IV infusion is a logical choice to overcome the short
half-life of the drug. Continuous intravenous infusion clearly has a
different spectrum of toxicity than bolus administration, as well as
a different maximum tolerated dose and achievable dose intensity.[5]
Cells resistant to bolus 5-FU occasionally remain sensitive to
continuous intravenous infusion, suggesting there may actually be a
different mechanism of action for that delivery system or that it
leads to a shift in the relative importance of each of the three
potential mechanisms for 5-FU discussed above. An alternate
explanation is that patients receiving continuous intravenous
infusion 5-FU achieve a 3- to 4-fold increase in cumulative dose vs bolus.[6]

Continuous intravenous infusion 5-FU, administered during radiation
therapy in the adjuvant treatment of rectal cancer, clearly leads to
improved survival over bolus therapy.[7] However, even in the absence
of radiation therapy, continuous intravenous infusion 5-FU remains
superior for the treatment of metastatic large bowel tumors. A recent
meta-analysis comparing the administration of 5-FU by continuous
intravenous infusion vs bolus found the response rate was
significantly higher for continuous intravenous infusion (22% vs
14%), which translated to a small overall survival benefit (hazards
ratio 0.88).[6] However, continuous intravenous infusion 5-FU is even
more inconvenient to administer, requiring a secure form of venous
access, as well as the use of an ambulatory infusion pump.

Fluorinated Pyrimidines With Radiation Therapy

Heidelberger and colleagues discovered that growth inhibitory doses
of radiation therapy in rodent tumors were made cytotoxic by the
addition of 5-FU. Conversely, ineffective 5-FU regimens became active
with the addition of a single fraction of radiation therapy.[8] These
synergistic effects have subsequently been confirmed by many other
investigators, using both in vitro and in vivo models.[9-15]
Randomized trials have demonstrated that the combination of 5-FU and
radiation therapy significantly improves local control and survival
for patients with a wide variety of solid tumors, compared to
radiation therapy or chemotherapy alone.[16-18]

The mechanism of 5-FU radiosensitization is poorly understood, and
the best timing for administration of the two modalities is not
precisely defined. There are several possible explanations for
radiation sensitization by 5-FU, and more than one type of
interaction is possible. FdUMP-mediated inhibition of thymidylate
synthase with resulting thymidine triphosphate (dTTP) pool depletion,
enhanced DNA damage, interference with DNA repair, and cell-cycle
effects all may contribute to radiosensitization. Indeed, some in
vitro models have shown that 5-FU increases the steepness of the
radiation survival curve, while others have demonstrated that 5-FU
reduces the shoulder of the curve (which represents the capacity for
DNA repair) without affecting the slope.[19] The underlying
mechanisms for the 5-FU/radiation-therapy interaction may be
influenced by drug dose, timing of administration, and duration of
5-FU exposure.

Byfield et al reported that combined treatment with 5-FU and
radiation therapy leads to time-dependent and dose-dependent
enhancement of cell killing in HeLa cervical cancer and HT-29 colon
cancer cells.[20] Enhanced radiosensitization was dependent on cell
exposure to 5-FU for periods longer than the cell-doubling time.
Optimal effects were observed when cells were exposed to 5-FU for 48
hours following radiation therapy, with little or no synergy observed
when the drug was given either before or for 3 to 24 hours after
radiation therapy. The authors concluded that radiation therapy
enhancement was not related to either an infliction of additional
acute damage by drug in the immediate post–radiation-therapy
period or to an inhibitory effect on repair of sublethal radiation-
therapy–induced damage.

Other investigators have suggested that alternate timing and modes of
5-FU administration can also lead to radiosensitization. Smalley and
associates reported that 5-FU modulation of radiosensitivity in
DU-145 human prostate cancer cells was evident with radiation therapy
delivered during a 1-hour pulse of 5-FU, as well as with radiation
therapy given either immediately before 5-FU or 17 hours after
5-FU.[19] Using a solid tumor model, Loony and associates observed
that maximal inhibition of tumor growth occurred when 5-FU was
administered 4 days after radiation therapy, with this combination
being 2.5-fold more effective than that expected if effects were
merely additive.[21] Beaupain and colleagues showed the
administration of 5-FU preceding radiation therapy to be the most
effective schedule in growth inhibition of human pulmonary cancer
nodules maintained in continuous organotypic culture.[22] Weinberg
and associates found no schedule dependency for 5-FU/radiation-therapy
enhancement in an in vitro squamous cell carcinoma model, though
there was clear dose dependency.[13] These studies clearly
demonstrate that there is substantial heterogeneity in cell
radiosensitivity modulation by 5-FU.

FUdR is an interesting drug with which to study
fluoropyrimidine-mediated radiosensitization. As a radiosensitizer,
FUdR is effective in concentrations at which it would only achieve
thymidylate synthase inhibition and would not demonstrate the more
complex interactions other fluoropyrimidines show with DNA and RNA.
Clearly, FUdR has been shown to be a potent radiosensitizer of HT-29
and HuTu80 human colon cancer cells.[23,24] Although sensitization
has been produced under a wide range of exposure conditions, FUdR is
substantially more effective when it precedes radiation therapy for 2
hours compared with when it follows radiation therapy. Sensitization
correlates with thymidylate synthase inhibition and depletion of dTTP
pools, and is blocked by coincubation with thymidine. However, 8- or
24-hour pre-exposures to low concentrations of FUdR can also enhance
radiation-therapy–induced DNA damage, apparently by inhibiting
repair of DNA double-strand breaks.

Both 5-FU and FUdR treatment arrest S-phase cells and block cells in
early S-phase (G1/S interphase) 16 to 32 hours following
fluoropyrimidine exposure. Early S-phase is thought to represent a
relatively radiosensitive portion of the cell cycle, but some
investigators have found that the fraction of cells in early S-phase
is a weak predictor of radiation therapy enhancement. Lawrence and
colleagues demonstrated that HT-29 cells with blocked S-phase
progression are not radiosensitized by FUdR.[24] Using a population
of synchronized HT-29 cells, McGinn and associates examined radiation
therapy survival data with FUdR and concluded early S-phase delay is
not the primary means of radiosensitization, although there is an
association between early S-phase enrichment and
radiosensitization.[25] Overall, experts suggest radiosensitization
is partially but not completely due to redistribution of cells
through the cell cycle, or at least to an alteration of the G1/S
check point.[26]

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