Heidelberger and associates synthesized fluorouracil (5-FU) in
1957 after observing that rat hepatomas utilized radiolabeled uracil
more avidly than malignant tissues. For the past 40 years, 5-FU has
been extensively investigated in various schedules, in combination
with biochemical modulators, and for a variety of malignancies.
Early in the clinical development of 5-FU, investigators noted
erratic bioavailability (0% to 80%) and unpredictable exposure and
toxicity associated with oral administration. Hence, the oral
administration of 5-FU was abandoned and clinical development focused
on intravenous schedules, including weekly bolus regimens, daily for
5 consecutive days, and protracted intravenous schedules.
Intravenous 5-FU schedules have been investigated primarily in
advanced colorectal cancer. Clinical research over the past 2 decades
has emphasized the use of 5-FU with the biochemical modulator,
leucovorin calcium. Unfortunately, trials in advanced colorectal
cancer reported modest gains in survivalwhich were not readily
reproducibleand poorly described effects on palliation and
quality of life.
These trials, however, have provided insight into the
schedule-dependent toxicities of 5-FU. Myelosuppression and oral
mucositis have been the consistent dose-limiting toxicities
associated with daily × 5 schedules, while diarrhea has been the
predominant serious toxicity associated with weekly schedules.
Hand-foot syndrome has been the dose-limiting toxicity of prolonged
Oral Fluorinated Pyrimidines
The review by Damjanov and Meropol highlights the clinical
development of oral fluorinated pyrimidinescapecitabine
(Xeloda), UFT (uracil and tegafur), S-1, and eniluracil plus oral
5-FU. These agents were developed to allow convenient prolonged oral
dosing of fluorinated pyrimdines while reducing toxicities such as
neutropenia and oral mucositis. Of these oral agents, capecitabine is
the only oral fluorinated pyrimidine approved by the Food and Drug
Administration (FDA). These agent received accelerated approval for
the treatment of refractory breast cancer patients. Subsequent
comments will focus on the three agents (capecitabine, UFT plus oral
leucovorin, eniluracil plus oral 5-FU) whose clinical development is
The oral fluorinated pyrimidines provide insights in the clinical
importance of dihydropyrimidine dehydrogenase (DPD), the initial and
rate-limiting catabolic enzyme of 5-FU. Eniluracil is an irreversible
inactivator of DPD; uracil (in UFT) provides competitive inhibition
of the enzyme, whereas capecitabine does not affect the enzyme.
Many oncologists are aware of this enzyme because of the clinical
condition associated with DPD deficiency that results in
life-threatening toxicity following treatment with conventional doses
of 5-FU.[3,4] In addition, variable DPD levelsthe result of
considerable interpatient differences in enzyme activity in the liver
and gastrointestinal (GI) tractmay be responsible for the
unpredictability of exposure to both oral and intravenous 5-FU. Rapid
intracellular catabolism of 5-FU by DPD has been suggested as a
mechanism of 5-FU resistance.
Catabolic end products of 5-FU have been implicated in the
pathogenesis of certain fluorinated pyrimidine toxicities. For
example, alpha-fluoro-beta-alanine (FBAL) has been found to be
neurotoxic in animal models and may have a role in producing the
neurotoxicity associated with fluorinated pyrimidines. In
addition, the poorly understood toxicity of hand-foot syndrome
associated with protracted 5-FU infusions and capecitabine is not
commonly observed in the fluorinated pyrimidines that inhibit or
inactivate DPD (ie, UFT and eniluracil). This contrasting profile of
toxicities has led to the speculation that the 5-FU catabolites may
be implicated in the pathogenesis of hand-foot syndrome.
Circumventing Erratic Absorption
Attempts to circumvent the erratic absorption of oral 5-FU have
focused on two different approaches. The first approach is to
inactivate DPDcoadministration of 5-FU with eniluracil
increases the bioavailability of 5-FU and provides greater
consistency in exposure. Eniluracil dramatically alters the systemic
disposition of 5-FU. In combination with eniluracil, the average
terminal half-life of 5-FU, which has been conventionally reported to
be 8 to 20 minutes, ranges from 4 to 6 hours.
The second method is to administer prodrugs of 5-FU, which are
converted to 5-FU after GI absorption. Both capecitabine and tegafur
(in UFT) are absorbed as prodrugs from the GI tract. Capecitabine
undergoes a three-step enzymatic conversion to 5-FU with the final
conversion being mediated by thymidine phosphorylase. Limited data
suggest that higher levels of this enzyme may be found in colorectal
tumors than in normal tissue.
Phase II trials of each of the fluorinated pyrimdines have
demonstrated a favorable toxicity profile and comparable efficacy to
reported data for intravenous 5-FU/leucovorin schedules. Each of
these three oral agents have been compared to standard
5-FU/leucovorin schedules in large phase III trials. End points have
included survival, response rates, time to progression, palliation of
prespecified symptoms, and quality of life. The trials have been
completed, and published results should be available in the near future.
Capecitabine, UFT, and eniluracil were developed when intravenous
5-FU/leucovorin was considered standard first-line
treatment of metastatic colorectal cancer. However, data from two
phase III randomized, controlled, multinational trials of irinotecan
(Camptosar) combined with 5-FU/leucovorin challenge 5-FU/leucovorin
alone as the preferred first-line treatment.
In both studies, the triple drug therapy of irinotecan and
5-FU/leucovorin resulted in statistically significant improvements in
survival, objective tumor response rates, and time-to-tumor
progression, as compared to results seen with 5-FU/leucovorin. These
differences in survival were maintained despite the fact that
approximately 30% to 40% of patients on the 5-FU/leucovorin arm
crossed over to irinotecan at the time of disease progression.[9,10]
The most clinically significant toxicities for patients receiving the
irinotecan-containing combinations were diarrhea, nausea, vomiting,
neutropenia, and alopecia. In one trial, grade 4 neutropenia,
neutropenic fever, and mucosititis were observed less frequently with
a weekly irinotecan combination than with monthly administration of 5-FU/leucovorin.[9,10]
Future Role of Fluoropyrimidines
The article reviewedOral Therapy for Colorectal Cancer:
How to Choosequestions the selection of an oral
fluorinated pyrimidine as the initial treatment of metastatic
colorectal cancer. However, the selection of first-line colorectal
cancer treatment has become more complicated in light of the survival
advantage associated with the triple-drug treatment of irinotecan
If the oral fluorinated pyrimdines demonstrate survival data
comparable to intravenous 5-FU/leucovorin, their optimal use in
colorectal cancer may need to be revisited. Future trials may
investigate combinations with irinotecan or other promising agents.
Their use in special patient populationssuch as elderly
patients or those with poor performance statuswho may not
tolerate ggressive therapies should be explored, focusing on
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4. Houyau P, Gay C, Chatelut E, et al: Severe fluorouracil toxicity
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5. Etienne MC, Cheradame S, Fischel JL, et al: Response to
fluorouracil therapy in cancer patients: The role of tumoral
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6. Zhang RWQ, Soong SJ, Liu TP, et al: Pharmacokinetics and tissue
distribution of 2-fluoro-beta-alanine in rats: Potential relevance to
toxicity pattern of 5-fluorouracil. Drug Metab Dispos 20:113-119, 1992.
7. Schilsky RL, Hohneker J, Ratain MJ, et al: Phase I clinical and
pharmacological study of eniluracil plus fluorouracil in patients
with advanced cancer. J Clin Oncol 49:1450-1457, 1998.
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Xeloda in colorectal cancer patients (abstract). Proc Am Soc Clin
Oncol 16:227a, 1997.
9. Douillard JY, Cunningham D, Roth AD, et al: A randomized phase III
trial comparing irinotecan + 5FU/folinic acid to the same schedule of
5-FU/FA in patients with metastatic colorectal cancer as front-line
chemotherapy (abstract). Proc Am Soc Clin Oncol 18:899, 1999.
10. Saltz LB, Locker PK, Elfring GL, et al: Weekly irinotecan,
leucovorin, and fluorouracil is superior to daily ´ 5 LV/FU in
patients with previously untreated colorectal cancer (abstract). Pro
Am Soc Clin Oncol 18:898, 1999.