Oral Fluoropyrimidine-Based Combination Therapy in Gastrointestinal Cancer

Oral Fluoropyrimidine-Based Combination Therapy in Gastrointestinal Cancer

ABSTRACT: Significant emphasis has been placed recently on designing more effective fluorouracil (5-FU)-based combination protocols for gastrointestinal cancer. Promising results were seen with 5-FU/leucovorin in combination with irinotecan (Camptosar) or oxaliplatin (Eloxatin), especially in colorectal cancer. Clinical trials of UFT, with or without leucovorin, demonstrate the safety of this regimen and an efficacy comparable to that of bolus 5-FU/leucovorin in the treatment of gastrointestinal tumors. Two large randomized phase III trials of capecitabine (Xeloda) showed that capecitabine also offers a convenient alternative to bolus 5-FU/leucovorin with a superior safety profile and at least equivalent antitumor activity. [ONCOLOGY 15(Suppl 2):79-84, 2001]


For the past 3 decades, fluorouracil (5-FU)-based
chemotherapy has been the mainstay of therapy for advanced gastrointestinal cancer. When
given alone to colorectal cancer patients as a weekly intravenous bolus or for 5
consecutive days every 4 to 5 weeks, 5-FU produced response rates ranging from
11% to 17% and was associated with a median survival of approximately 1
year.[1-3] Although the increased efficacy of 5-FU (in terms of higher response
rates) via biomodulation with leucovorin has been well established, a
meta-analysis of clinical studies failed to demonstrate a clear survival

Moreover, evidence has accumulated that prolonged infusion of
5-FU may improve its antitumor effect when compared with 5-FU bolus
regimens.[6,7] However, no significant differences in overall survival time were
found when bolus 5-FU, administered according to the North Central Cancer
Treatment Group (NCCTG)-regimen, was given with one of several 5-FU regimens
including infusional 5-FU.[8] These data correspond with the recent results of a
randomized trial conducted by the European Organization for Research and
Treatment of Cancer (EORTC-GICCTG) that compared low-dose leucovorin-modulated
bolus 5-FU with a weekly schedule of high-dose infusional 5-FU/leucovorin in
patients with metastatic colorectal cancer.[9] Thus, significant emphasis has
been placed on designing more effective 5-FU-based combination protocols.
Promising results were achieved recently with combinations of 5-FU/leucovorin
and either irinotecan (CPT-11, Camptosar) or oxaliplatin (Eloxatin). These
combinations proved superior to conventional 5-FU/leucovorin schedules,
especially in colorectal cancer.[10-16]

Combination Protocols

Irinotecan and Fluorouracil

For the combination of irinotecan and 5-FU, three schedules were
carried forward in two large randomized phase III trials: (a) irinotecan at 125
mg/m2, leucovorin at 20 mg/m², and 5-FU at 500 mg/m2 on a weekly
´ 4
schedule (Saltz regimen),[17] (b) irinotecan at 80 mg/m2 in combination with
leucovorin at 500 mg/m2 (2-hour infusion), and 5-FU at 2.6 g/m2 (24-hour
infusion) on a weekly ´ 6 schedule (AIO schedule),[18] or (c) the biweekly
schedule of irinotecan at 180 to 200 mg/m2 in combination with
leucovorin-modulated infusional 5-FU administered according to the de Gramont
schedule (leucovorin at 200 mg/m2 (2-hour infusion), followed by 400 mg/m2 of
5-FU bolus, and then 600 mg/m2 of 5-FU by continuous infusion over 22 hours on
days 1 and 2 every 14 days).[19]

Saltz Regimen

In the first trial, the weekly ´ 4 regimen of irinotecan and
bolus 5-FU/leucovorin (Saltz regimen) was compared with conventional low-dose
leucovorin/5-FU (Mayo-Clinic protocol).[12] In an intent-to-treat analysis,
treatment with the combination of irinotecan and 5-FU/leucovorin resulted in a
significantly higher remission rate (P < .001), significantly longer
progression-free survival time (P = .004), and significantly longer median
survival (P = .04) when compared to leucovorin/5-FU alone. National Cancer
Institute Common Toxicity Criteria (NCI-CTC) grade 3 and 4 diarrhea was observed
in 23% of patients in the combination arm and 13% of patients treated with
leucovorin/5-FU alone. On the other hand, there was a significantly higher
incidence of grade 4 neutropenia (42%) in patients receiving 5-FU/leucovorin
alone compared to those receiving irinotecan/5-FU (24%). Furthermore, it could
be demonstrated that treatment with the combination of
irinotecan/leucovorin/5-FU had no detrimental effect on overall quality of life
and global health status compared to 5-FU/leucovorin alone.

AIO Schedule or
de Gramont Regimen

The second randomized trial used two forms of 5-FU infusion,
either the weekly ´ 6 schedule of high-dose leucovorin followed by a 24-hour
infusion of 2.3 g/m2 of 5-FU (AIO schedule) or the biweekly de Gramont
regimen.[13] Participating centers had to choose one of the two schedules. In
the experimental arm, irinotecan was added to the same 5-FU infusion protocol
(80 mg/m2 per week for the AIO schedule or 180 mg/m2 every 2 weeks for the de
Gramont schedule).

A response rate of 41% was achieved with the combination
compared to 23% with leucovorin/5-FU alone (P < .001). Moreover, the median
time to disease progression (P < .001) and median survival (P < .028)
showed a significant advantage for the combination arm with irinotecan vs the
control arm. The incidence of grade 3 and 4 neutropenia was higher in the
irinotecan/5-FU arm, but did not translate into a significantly higher incidence
of either neutropenic fever or infection. There was also slightly more grade 3
and 4 diarrhea (24% of patients) in the combination arm compared to
leucovorin/5-FU alone (11% of patients).

Oxaliplatin Combinations

Oxaliplatin, a trans-l-1-diaminocyclohexan-oxalato
[DACH]-platinum analog, has also shown efficacy in colorectal cancer.[10]
Oxaliplatin in combination with leucovorin/5-FU given either chronomodulated or
in accordance with the de Gramont schedule has been compared to the same
leucovorin/5-FU regimen alone in two randomized multicenter phase III
trials.[15,16] The combination of oxaliplatin with leucovorin/5-FU significantly
improved overall response rate and median time to disease progression in both
trials; however, median survival was not significantly prolonged in these

UFT Combinations

UFT is an orally administered fixed combination of tegafur and
uracil in a 1:4 molar ratio. Tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil) is
absorbed intact via the gastrointestinal tract and is then converted to 5-FU by
hepatic microsomal cytochrome P450 enzymes, as well as through soluble enzyme
hydrolysis. Uracil is a competitive inhibitor of dihydropyrimidine dehydrogenase
(DPD). Preclinical studies demonstrated that the addition of uracil to tegafur
in these concentrations significantly increased the tumor-to-serum and
tumor-to-normal tissue ratios of 5-FU.[3,20,21] Co-administration of leucovorin
to UFT further enhanced the activity of UFT as shown in preclinical and clinical

The results of clinical trials demonstrate that UFT, with or
without leucovorin, can be safely administered over weeks and even months. The
compound is associated with a favorable toxicity profile compared to bolus
5-FU/leucovorin, with diarrhea being the main toxicity.[23,24]

UFT, with or without leucovorin, induces overall response rates
in gastrointestinal tumors comparable to those achieved with bolus
5-FU/leucovorin.[20,23-29] These experiences prompted further investigation of
UFT as part of combination chemotherapies in esophageal, gastric,
pancratico-biliary tract, and colorectal cancers.


Capecitabine (Xeloda)
(N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidine
carbamate that is converted to fluorouracil by three enzymes located in the
liver and tumor tissue.[30,31] The final step is the conversion of
5'-deoxy-5-fluorouridine (5'-dFUrd) to 5-FU by thymidine phosphorylase
preferentially in tumor tissue.

The high thymidine phosphorylase expression in tumor cells
selectively enhances 5-FU concentrations, and may result in higher antitumor
activity and decreased drug levels in nontumor tissue, with a consequent
reduction in systemic toxicity.[32] Preclinical studies on human tumor
xenografts suggest that the antitumor efficacy of capecitabine is superior to
that of UFT or 5-FU. In these in vivo models, capecitabine was less toxic to the
intestinal tract, indicating a higher therapeutic potential.[31] Capecitabine is
associated with significant antitumor efficacy in various malignancies,
including colorectal cancer and breast cancer.[33-36]

In two large randomized trials in metastatic colorectal cancer,
capecitabine was significantly superior to bolus 5-FU/leucovorin (Mayo Clinic
protocol) in terms of response rate (25.7% vs 16.7% confirmed responses; P <
.0002 [integrated results of 1,207 patients]).[37] However, in both trials no
significant differences in time to disease progression and overall survival were
observed between capecitabine and bolus 5-FU/leucovorin (time to progression:
4.6 months vs 4.7 months, respectively, and overall survival time 12.9 months
for both).

Although hand-foot-syndrome occurred more often in patients
receiving capecitabine than in those receiving bolus 5-FU/leucovorin, it
resulted in only two hospitalizations. Furthermore, the treatment-related
hospitalization rate was significantly reduced in patients treated with
capecitabine. The results of the integrated analysis of both trials demonstrate
that capecitabine offers a convenient alternative to bolus 5-FU/leucovorin with
a superior safety profile and equivalent antitumor efficacy.

Considering the antitumor activity and safety profile of the
oral fluoropyrimidine prodrugs (UFT, capecitabine), different combinations with
other cytotoxic agents active in gastrointestinal cancer, such as mitomycin C
(Mutamycin), irinotecan, and the platinum analogs are currently under clinical
investigation in gastrointestinal cancer.


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