Oral Therapy for Colorectal Cancer: How to Choose
Oral Therapy for Colorectal Cancer: How to Choose
Colorectal cancer is the fourth most common
malignancy diagnosed in the United States and the second most common
cause of cancer death. For several decades, fluorouracil (5-FU) stood
alone as the only agent with clinical activity against colorectal
cancer. Even with the introduction of irinotecan (Camptosar) and
oxaliplatin, 5-FU remains a component of standard adjuvant therapy
and the initial management of metastatic disease.
Because of its incomplete and erratic oral bioavailability, 5-FU is
commonly administered intravenously. However, patients prefer oral
rather than intravenous therapy, with oral treatment potentially
more convenient and less costly. Thus, methods to effectively deliver
fluorinated pyrimidines orally have recently been developed.
Two general approaches have been undertaken. The first involves the
use of prodrugs that are absorbed intact in the gastrointestinal
tract and are ultimately converted to 5-FU in normal or tumor
tissues. Examples of this method of oral administration are
capecitabine (Xeloda) and tegafur, a component of UFT and S-1 (Figure
An alternate approach of delivering 5-FU by the oral route is to
block its gastrointestinal degradation via coadministration of an
inhibitor of dihydropyrimidine dehydrogenase (DPD), the rate-limiting
enzyme in 5-FU catabolism. Inhibitors of DPD in clinical development
include eniluracil; uracil, a component of UFT; and
5-chloro-2,4-dihydroxypyridine (CDHP), a component of S-1 (Figure
Preclinical models suggest an improved therapeutic index with
administration of oral fluoropyrimidines. This observation has fueled
rapid clinical development of these agents over the past 5 years.
Heidelberger et al first synthesized 5-FU in 1957, designing a
pyrimidine antimetabolite that also inhibits thymidylate synthase
(TS). Following intravenous administration, 5-FU undergoes both
anabolism and catabolism (Figure 2).
Within minutes, 80% of the drug is catabolized to the inactive
dihydro-5-FU. This conversion is mediated by dihydropyrimidine
dehydrogenase (DPD), an enzyme found predominantly in the liver but
widely present in other human tissues. The remaining 20% of 5-FU is
anabolized to the active species responsible for cytotoxicity. Figure
2 shows the steps in the formation of the cytotoxic metabolites
Mechanisms of Action
Three distinct mechanisms of action of 5-FU have been described.
Fluorouracil is converted to fluorodeoxyuridine (FUdR) by thymidine
phosphorylase. Fluorodeoxyuridine is then phosphorylated by thymidine
kinase to fluorodeoxyuridine monophosphate (FdUMP).
Fluorodeoxyuridine monophosphate forms a stable covalent complex with
TS in the presence of the reduced folate cofactor,
5,10-methylenetetrahydrofolate. This inhibition of TS prevents the
formation of deoxythymidine monophosphate (dTMP) from deoxyuridine
monophosphate (dUMP) and thereby decreases the availability of
deoxythymidine triphosphate (dTTP) for DNA replication and repair.
In addition to decreasing the availability of dTTP, the inhibition of
TS causes an increase in the amount of dUMP available in the cell.
Deoxyuridine monophosphate, like FdUMP, can be anabolized to the
triphosphate level. Fluorodeoxyuridine triphosphate (FdUTP) and
deoxyuridine triphosphate (dUTP) can be incorporated into DNA,
contributing to the inhibition of DNA elongation and altering DNA
Furthermore, fluorouridine monophosphate (FUMP) is formed from 5-FU
by either the sequential actions of uridine phosphorylase and uridine
kinase, or the direct action of orotate phosphoribosyltransferase
(OPRT) in the presence of phosphoribosylpyrophosphate (PRPP).
Subsequently, FUMP is phosphorylated to form fluorouridine
diphosphate (FUDP) and then fluorouridine triphosphate (FUTP). The
triphosphate is incorporated into nuclear and cytoplasmic RNA,
thereby interfering with normal RNA processing and function.
Fluorouracil has been investigated extensively in the treatment of
colorectal malignancies. However, response rates to 5-FU alone rarely
exceed 20%. Attempts to improve the efficacy of 5-FU without
increasing morbidity have included the addition of biochemical
modulators and alterations in administration schedules.
The most successful example of biochemical modulation of 5-FU is the
addition of reduced folates in the form of leucovorin to stabilize
the ternary complex of FdUMP and TS. A meta-analysis of trials
comparing 5-FU alone to 5-FU plus leucovorin found an improved
response rate in patients with metastatic colorectal carcinoma
treated with the combination (11% vs 23%; P < 10-7).
However, there was no impact on overall survival; median survival in
patients treated with 5-FU alone was 11 months, compared with 11.5
months in those given 5-FU plus leucovorin.
Many administration schedules of 5-FU have been tested. They differ
in patterns of toxicity; however, none of these regimens has
demonstrated a major survival advantage.
A recent meta-analysis compared bolus 5-FU (with or without
leucovorin) to protracted venous infusions of 5-FU in patients with
metastatic colorectal cancer. This analysis, which combined six
clinical trials involving 1,219 patients, found an overall response
rate of 22% in the patients who received continuous-infusion 5-FU, as
opposed to a rate of 14% in patients treated with bolus 5-FU.
Patterns of toxicity differed, with severe hematologic toxicity more
common with bolus treatment, and hand-foot syndrome more common with
infusional therapy. However, there was only a minimal difference
in median survival (12.1 months with bolus treatment vs 11.3 months
with infusional therapy; P = .04).
Rationale for Developing Oral Agents
In a survey study of cancer patients, Liu et al found that
patients prefer oral rather than intravenous treatment, but are
unwilling to sacrifice tumor response for ease of administration. In
this study of 103 patients, 89% stated a preference for oral therapy.
Reasons for this choice included convenience and fewer problems with
venous access. Nevertheless, 70% of survey respondents were unwilling
to accept a lower response rate with oral therapy. Thus, although
convenience is an important potential advantage, therapeutic
equivalence or superiority is required of oral agents.
Daily oral therapy also has the potential to mimic the pharmacology
of protracted intravenous infusions of 5-FU, without the cost,
complications, and inconvenience of ambulatory infusion pumps. Given
some evidence of an improved therapeutic index for protracted
infusion schedules in colorectal cancer,[8-11] the recent clinical
development of oral fluoropyrimidines has focused on continuous daily schedules.
Traditionally, efforts at biochemical modulation of 5-FU activity
have focused on anabolic pathways. The most successful example of
this approach is the use of leucovorin to improve the inhibition of
TS by FdUMP.
Recently, however, the role of 5-FU catabolism in toxicity and
resistance was recognized. This led to the identification of a new
target for biochemical modulation, namely, the enzyme DPD. This rate-limiting
enzyme in 5-FU catabolism accounts for 5-FUs serum half-life
of approximately 15 minutes.
In patients with a congenital deficiency of DPD, treatment with
standard doses of 5-FU results in severe and life-threatening
toxicity associated with prolonged half-life and renal excretion.
Intestinal expression of DPD accounts for the poor oral
bioavailability of 5-FU. In animal models, the 5-FU catabolite
dihydrofluorouracil has been associated with toxicity and tumor
resistance.[13,14] Furthermore, DPD levels in human tumor tissue have
been correlated with clinical resistance to 5-FU.
These observations led to the development of DPD inhibitors as
biochemical modulators of 5-FU in the hope that inhibition of DPD
would permit effective oral administration of 5-FU with an improved
therapeutic index compared to intravenous treatment.