Since the late 1980s, a series of randomized
clinical trials, including meta-analyses, have assessed various
schedules and combinations of 5-fluorouracil (5-FU)-based therapy for
the treatment of advanced colorectal cancer. A smaller series of
studies has evaluated the role of intra-arterial chemotherapy for
patients with metastatic colorectal cancer to the liver. Results of
these trials have helped define the appropriate comparison regimens
for the next generation of studies using new agents, eg, irinotecan
(CPT-11) and the oral dihydropyrimidine dehydrogenase (DPD) inhibitor
eniluracil plus oral 5-FU. This review summarizes significant
randomized trials and published meta-analyses involving advanced
colorectal cancer, including trials of 5-FU plus leucovorin, continuous-infusion
5-FU, and intra-arterial fluoropyrimidines.
The mechanism of action of 5-FU depends on two active metabolites,
5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouracil
triphosphate (FUTP). The intracellular conversion of 5-FU to FdUMP
results in the inhibition of the enzyme thymidylate synthase (TS)
through formation of the covalent ternary complex (TS-FdUMP and 5, 10
methylene tetrahydrofolate) (Figure 1).[1,2]
For more than 10 years, randomized trials in colorectal cancer have
focused on this particular 5-FU metabolic pathway, best exemplified
by modulation of 5-FU by leucovorin. Preclinical investigations
suggest that interferon-alfa biochemically modulates 5-FU by
increasing intracellular levels of FdUMP and by binding to TS.
Furthermore, continuous-infusion 5-FU results not only in a greater
proportion of tumor cells exposed to the drug, but also may enhance
cytotoxic activity by inhibition of TS. In contrast,
N-(phosphonacetyl)-L-aspartic acid (PALA) blocks de novo pyrimidine
synthesis pathways by inhibiting aspartate transcarbamylases.
Combining PALA with 5-FU enhances tumor cytotoxicity by increasing
the incorporation of 5-FU into RNA.
More recently, significant interest has focused on strategies to
inhibit 5-FU degradation pathways. The major pathway of 5-FU
catabolism is via the enzyme DPD, producing the inactive metabolite a-fluoro-b-alanine.
The variability in oral bioavailability of 5-FU is due to
substantial variation in DPD activity in the GI tract during first
pass metabolism of the drug. Eniluracil is a potent irreversible
inactivator of DPD, which substantially increases the plasma
half-life and bioavailability of oral 5-FU.[3-7] This agent allows
long-term oral administration of 5-FU, which may provide results
similar to those achieved with continuous intravenous infusion 5-FU.
Results of two large randomized trials, assessing modulation of 5-FU
and toxicities with various schedules and combinations, were recently
reported.[8,9] The Southwest Oncology Group (SWOG) randomized phase
II study included 620 patients who received one of seven 5-FU-based
regimens, including bolus 5-FU, bolus 5-FU with either low-dose or
high-dose leucovorin, protracted venous infusion 5-FU with or without
low-dose leucovorin, and high-dose 24-hour infusional 5-FU with or
without PALA (Figure 2). The
trial was designed to screen these regimens and to select those
producing the best response or survival for a randomized phase III
Results showed that patient characteristics were comparable in all
treatment groups. The majority of patients had an ECOG performance
status of 0-1 and most had not received previous adjuvant therapy.
Differences in toxicities were noted among the treatment groups. In
particular, more patients (47%) who received bolus 5-FU with or
without low-dose leucovorin experienced grade 3 and 4
granulocytopenia compared with patients (1%) who received low-dose
continuous-infusion 5-FU with or without leucovorin. Diarrhea
occurred most frequently in patients receiving high-dose leucovorin.
Seventy-one percent of accrued patients had measurable disease.
Confirmed response rates ranged from 13% to 24% (15% to 29% when
unconfirmed responses were included). At a median follow-up duration
of 37 months, there was minimal difference among the seven regimens
with respect to progression-free survival. A survival trend was
noted, however, favoring the low-dose continuous infusion and 24-hour
infusion 5-FU regimens, whereas patients who received PALA plus
high-dose infusional 5-FU had a shorter survival duration. Overall
survival ranged from 13 to 15 months for all treatments.
Interpretation of these results is complex because, paradoxically,
patients receiving single-agent bolus 5-FU had higher than expected
response and survival rates as compared with historical data (29% vs
an expected response of 11%). No clear explanation accounts for this
high response rate, though it is possible that patients with
excellent performance status and metastatic disease were diagnosed
earlier than those in previous trials. Variations in response rate
may also be secondary to dose intensity. For example, only 48% of
patients receiving high-dose leucovorin received 100% of the planned
dose, usually due to toxicity. The authors concluded that infusional 5-FU
produced the most favorable toxicity spectrum and the longest
survival, warranting further investigation in phase III trials.
The Eastern Cooperative Oncology Group (ECOG) in collaboration with
the Cancer and Leukemia Group B (CALGB) recently accrued 1,072
patients in a five-arm randomized phase III trial designed to
evaluate the role of biochemical modulation therapy for patients with
advanced colorectal cancer (Figure 3).
Among evaluable patients, 62% were male and 38% female; 65% had
measurable disease (701 patients) and 35% had nonmeasurable disease
(371 patients). Performance status (ECOG) was 0 in 53% and 1 or 2 in
47% of patients. Hepatic metastases were present in 74% of patients,
and 89% (955 patients) had received no previous chemotherapy.
Four pair-wise comparisons were included in the analysis; high-dose
infusional 5-FU vs PALA with the infusion, 5-FU with IV vs oral
leucovorin, high-dose infusional 5-FU vs 5-FU and IV leucovorin, and
5-FU and IV leucovorin vs 5-FU and interferon. A preliminary analysis
demonstrated no significant survival differences among the
comparisons (median survival range, 11.9 to 15.3 months). Significant
differences in toxicity, however, were apparent. The 5-FU and
interferon regimen produced more grade 3 or 4 toxicities and
stomatitis (26%) compared with the other four regimens. The incidence
of severe diarrhea was significantly increased in patients receiving
leucovorin-containing regimens; up to 36% of patients receiving IV
leucovorin experienced grade 3 or 4 diarrhea. Overall, the high-dose
infusional 5-FU arms produced significantly less grade 3 or 4
toxicity compared with the leucovorin- and interferon-based regimens.
Significant differences in survival by patient characteristics were
also noted. For example, median survival was 16.9 months for patients
with nonmeasurable disease compared with 12.6 months for those with
measurable disease (P = .0001). Likewise, median survival was 15.9
months in patients with a performance status of 0 and 11.9 months if
performance status was ³ 1 (P =
.0001). Furthermore, patients with hepatic metastases had a median
survival of 13.3 months vs 15.7 months for those without hepatic
metastases (P = .0002).
In summary, the results of this large definitive trial demonstrated
that 5-FU modulated by leucovorin or interferon was more toxic and
not more effective than 5-FU given as a 24-hour high-dose infusion
weekly. Oral leucovorin provided no advantage over IV dosing. The use
of PALA at this dosing schedule did not enhance the activity of
weekly infusional 5-FU. In addition, this trial confirmed that the
presence of measurable disease, hepatic metastases, or
disease-related symptoms is associated with a poorer prognosis.
Two published meta-analyses have addressed the effect of 5-FU
treatment on objective tumor response and survival in advanced
colorectal cancer. One compares 5-FU and leucovorin vs 5-FU alone;
and the other, 5-FU via continuous intravenous infusion vs bolus administration.[10,11]
The Advanced Colorectal Cancer Meta-Analysis Project included nine
randomized trials comparing 5-FU alone to IV leucovorin and 5-FU,
given either weekly or daily for 5 days. A tenth trial conducted by
the North Central Cancer Treatment Group (NCCTG)/Mayo Clinic was
included using published results for response and survival analyses.
Individual patient data were not available from this trial. The
numbers of patients varied from 53 to 382 patients per trial, all
with measurable disease. The eligibility and response criteria used
in the trials were comparable. Differences in the patient populations
between trials included fewer patients with liver metastases only in
the two US trials (Northern California Oncology Group [NCOG], City of
Hope) compared with the others; and in eight of the nine trials, more
than two thirds of the patients had a good performance status (<
2) while in one trial (Bologna) almost three fourths of patients had
performance status ³ 2. Finally,
fewer patients in the NCOG trial than in the other trials had rectal
Overall, 1,381 patients were randomized in the nine clinical trials.
The mean follow-up was 13 months. Objective responses were seen in
11% of patients receiving 5-FU and 23% of those receiving 5-FU +
leucovorin (P < 10-7) (Figure 4).
The odds ratios favored the 5-FU and leucovorin combination in seven
of the nine trials (odds ratio ranges, 0.18 to 1.21). There was no
survival advantage of 5-FU + leucovorin over 5-FU alone (P = .57) (Figure
An evaluation of individual prognostic factors demonstrated that
patients with a good performance status or metastases confined to the
liver had significantly better survival (P <10-9 and P
= .046, respectively). In contrast, the NCCTG/Mayo trial showed
improved objective tumor responses for patients receiving
leucovorin-containing regimens and a statistically significant
advantage in overall survival for both high-dose and low-dose
leucovorin (P = .037 and P = .050, respectively). Survival benefit,
however, was limited to patients with nonmeasurable disease.
One conclusion of this trial was that tumor response is not a valid
surrogate end point for survival when planning clinical trials for
advanced colorectal cancer. Hypotheses to explain why the response
benefit with 5-FU + leucovorin did not translate into improved
survival included the following: The response duration may have been
too brief to affect survival, and/or the response rate to 5-FU +
leucovorin may have been too small to affect survival, since 75% of
patients did not respond. Therefore, even with the meta-analysis,
there may have been too few patients to detect significant survival
differences between treatment groups. Another question is whether
there was a crossover effect for patients who received 5-FU +
leucovorin after progressing on 5-FU therapy.
The Meta-Analysis Group in Cancer recently published an analysis of
1,219 patients entered onto six randomized trials, each comparing
continuous-infusion 5-FU given at various schedules with bolus 5-FU,
usually administered daily× 5. In two of the trials,
leucovorin was added to both the infusion and bolus regimens. Results
showed that continuous-infusion 5-FU resulted in a statistically
significantly higher response rate than bolus 5-FU (22% vs 14%;
overall response odds ratio, .55; 95% confidence interval [CI],
.41-.75; P = .0002) (Figure
6). Overall survival was also significantly higher for patients
receiving continuous-infusion 5-FU (overall hazards ratio, .88; 95%
CI, .78-.99, P = .04) (Figure 7).
Multivariate analysis demonstrated that patients with good
performance status had improved tumor response and survival (P <
.0001, P < .0001, respectively), and that patients with rectal
cancer as the primary tumor site had improved survival compared with
those with colon cancer (P = .0003). Therefore, significant
predictors of tumor response were treatment and performance status,
and significant predictors of survival were treatment, performance
status, and primary tumor site. Grade 3 or 4 hematologic toxicity
occurred more frequently in patients receiving 5-FU bolus therapy
(31% vs 4%; P < 10-16). Erythrodysaesthesia was seen
more frequently in the continuous-infusion 5-FU-treated group (34% vs
13%; P < 10-7). The authors concluded that
continuous-infusion 5-FU was superior to 5-FU bolus therapy, both for
tumor response and survival (though the magnitude of the survival
benefit was small), and that continuous-infusion 5-FU was less toxic
than bolus treatment.
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