Fluorouracil (5-FU) has been the mainstay
of treatment for colorectal cancer in the US for the past 40 years, primarily
because no other agents with significant activity in colorectal cancer have been
available. As a result, researchers focused on optimizing 5-FU therapy with two
main strategies. The first was to add agents to 5-FU in a logical,
biologically-based fashion that generates an enhanced anticancer response.
Agents tested include leucovorin, methotrexate (Folex, Mexate),[2,3]
trimetrexate (Neutrexin), PALA (Sparfosate sodium), IUdR, AZT,
interferon, and many others. This strategy of biochemical modulation
succeeded in generating improvements in response rates over single-agent
The second major avenue of research altered the treatment
schedule for 5-FU. Traditionally, 5-FU was administered as a bolus infusion and,
consequently, was associated with a distinctive efficacy and side effect
profile. However, when 5-FU is infused over a prolonged period, an alternate
efficacy and toxicity profile emerges. An extreme example of this strategy
is the use of chronomodulated infusional 5-FU in an attempt to take advantage of
diurnal variations in the metabolism of this agent.
Multiple studies, including meta-analyses, have been performed
comparing bolus schedules of 5-FU with prolonged infusion schedules in colon
cancer patients.[12,13] The evidence suggests that infusional schedules are less
toxic, have higher response rates, and improve survival, compared with bolus
schedules (Table 1). Major reasons for the lack of widespread use of continuous
infusion 5-FU center around the inconvenience of prolonged infusion therapies
and enhanced physician and patient care demands. The development of an orally
bioavailable compound may circumvent these problems and lead to superior therapy
for patients with colon cancer.
Because it is rapidly and inconsistently metabolized by
dihydropyrimidine dehydrogenase (DPD), it is not feasible to use 5-FU orally.
Several approaches have been pursued in an attempt to bypass DPD metabolism and
create an orally bioavailable compound. One approach involves the use of agents
that inhibit or compete directly with DPD and, in a sense, "level the
playing field" so that 5-FU becomes orally bioavailable.[14,15]
The agent capecitabine (Xeloda) approaches this problem in a
different way. This compound was designed to be resistant to DPD metabolism in
its native form. However, through a series of enzymatic steps within the body
and a final step within tumor cells, capecitabine is metabolized to become
5-FU. Essentially, it is selectively activated within tumors as 5-FU,
resulting in reduced systemic exposure and toxicity while maintaining high
concentrations of intratumoral 5-FU.
There is considerable interest and debate surrounding the
history of these oral 5-FU agents, and in this article, I will review the
development and clinical experience of capecitabine in colorectal cancer. The
successful evolution of these compounds has resulted in a more convenient method
of administering 5-FU, a lower toxicity profile, and a significantly higher
response rate in patients with metastatic colon cancer when compared to IV 5-FU.
Three phase I trials of single-agent capecitabine using three
different treatment schedules were performed in patients with a variety of
malignant tumors. One involved prolonged continuous exposure using twice-daily
dosing without interruptions. A second used capecitabine alone in a
2-week-on and 1-week-off schedule. The third used a similar intermittent
schedule, but with the addition of leucovorin. These studies found that the
intermittent schedules allowed administration of higher doses of capecitabine
but resulted in greater hand-foot syndrome. Diarrhea was reported as the
dose-limiting toxicity in all treatment schedules.
An early clinical trial was performed in patients with colon
cancer to prove that (1) the key activating enzyme, thymidine phosphorylase
(TP), is indeed overexpressed within tumors as compared to normal tissues, and
(2) that capecitabine is selectively activated within tumors resulting in higher
5-FU concentrations. The study was designed to treat patients who were
scheduled to undergo resection of either their primary colon cancer or a
metastasis with a preoperative course of capecitabine 2500 mg/m2 split into two
daily doses for 5 to 7 days. Resections were performed within 12 hours after
administration of the last dose.
Phase I Results
The resected specimens were then analyzed for levels of TP and
5-FU. Comparisons were made between tumor, and surrounding normal tissue, and
plasma. The results strongly support the theory that capecitabine is selectively
activated within tumors. First, tumor tissues markedly overexpress TP when
compared to normal tissues (with the exception of normal liver, which also
express high levels of TP). In an exact parallel, 5-FU levels were markedly
higher in tumors compared to surrounding tissue and plasma, and again, the liver
was the exception with fairly high levels of 5-FU. In fact, when the
concentrations of 5-FU in tumor were compared to those within the plasma, a
twenty-fold increase in 5-FU was found within tumors (Figure
These data have been compared to similar analyses of IV 5-FU,
which demonstrated that, following intravenous administration of 5-FU in colon
cancer patients, there are higher concentrations of 5-FU in circulating plasma
than in the tumor. Therefore, this study strongly supported the importance
of mechanisms of selective activation and increased delivery of 5-FU to the
As reviewed above, several schedules emerged from the phase I
trials, each having advantages and disadvantages. In order to define the optimum
schedule to carry forward into more definitive phase III trials, a randomized
phase II trial was performed comparing the three leading schedules of
capecitabine in colorectal cancer. A summary of the trial design is shown in
Figure 2. This trial was performed in patients with metastatic colon cancer who
had received no previous therapy. Patients were randomized to one of three
schedules of capecitabine. The end points of the trial were response rates and
toxicity, and an analysis for dose intensity was also performed.
Results demonstrated no difference in survival among the three
treatment arms. However, there was significant improvement in time to disease
progression in the patients who received capecitabine alone on an intermittent
schedule as seen in Table 2. As predicted, the higher dose, intermittent
schedules resulted in greater toxicity, particularly diarrhea and hand-foot
syndrome, when compared with the lower-dose continuous infusion schedule. The
intermittent schedule without leucovorin was selected for the phase III
randomized trials based on the improved time to disease progression, the higher
dose intensity, and the better therapeutic index associated with that regimen.
Two phase III trials were conducted comparing capecitabine to
intravenously administered 5-FU and leucovorin in patients with previously
untreated metastatic colorectal cancer. One trial was performed primarily in
Europe and the other, primarily in North America. The design of the
trials was identical and each was powered to show equivalence in overall
response rate between capecitabine and IV 5-FU/leucovorin. Secondary objectives
included a comparison of the toxicity, time to disease progression, overall
survival, time to response, quality of life, and duration of response.
At the time the trials were designed, the standard of care for
front-line treatment of metastatic colon cancer was the Mayo Clinic schedule of
5-FU and leucovorin5-FU 425 mg/m2 plus leucovorin 20
intravenously for 5 days every 28 days. This regimen was therefore selected as
the control arm for both of these studies. The standard criteria for phase III
randomized trials in this disease population established eligibility for these
studies. Tumor responses were analyzed by the investigators and by an
independent group of radiologists, who were blinded. Tumor assessment was based
on WHO criteria.
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