Fluorouracil (5-FU) is one of the most
extensively investigated chemotherapy agents in medical oncology.
Generations of medical oncologists have equated this agent with the
optimal treatment of colorectal cancer, both in the advanced and
5-FU has been examined in multiple schedules and also with agents to
modulate its activity biochemically. 5-FU has well-described
schedule-dependent toxicities. Many of these toxic effects can be
reduced with protracted intravenous schedules. Although protracted
5-FU infusion reduces the toxicities of neutropenia, mucositis, and
diarrhea, there is a clinical trade-off with its use
because hand-foot syndrome emerges as a novel toxicity. Also,
patients are inconvenienced with portable infusion pumps and
experience complications associated with indwelling central venous
catheters, such as line slippage, infection, and thrombosis.
The biochemical modulation of 5-FU has focused on calcium leucovorin.
Regimens of 5-FU plus leucovorin improve response rates and may exert
a small effect on overall survival when compared to bolus 5-FU
schedules. Results of large, randomized clinical trials examining
5-FU plus leucovorin regimens remind oncologists that only a minority
of patients receive benefit from our therapy as assessed by response
rates. Unfortunately, the median survival of patients with metastatic
colorectal cancer hovers around 12 months. Toxic effects of our
best schedules of intravenous 5-FU and leucovorin are not
trivial, with over one-fourth of patients experiencing either grade 3
or 4 neutropenia, stomatitis, or diarrhea.
Oral fluorinated pyrimidines have been extensively prescribed in
Japan for both the adjuvant and palliative treatment of a wide array
of malignancies, including gastric, breast, colorectal, lung, and
head and neck cancers. The extensive use of these oral agents in a
variety of malignancies and their prolonged use in individual
treatment courses reflect inherent differences between oncology care
delivery in Japan and the United States. Nevertheless, these agents
provide oral delivery of 5-FU in a consistent, reliable manner.
Schedules can be developed that minimize the toxic effects of 5-FU.
UFT, a combination of uracil (which competitively inhibits 5-FUs
catabolism) and tegafur (a 5-FU prodrug), is the most widely used
chemotherapy agent in Japan.
In the United States, we began our investigation of UFT almost a
decade ago. Little was known about the agent outside of Japan, with
the exception of clinical trials performed in Spain where UFT was
commercially available. Trials were initiated examining UFT as a
single agent. Attempting to optimize the advantages of an oral
therapy, prolonged oral schedules of UFT were developed to provide a
continuous fluorouracil exposure, without the attendant catheter and
infusion pump problems associated with protracted intravenous 5-FU infusions.
Because of the extensive preclinical and clinical investigations
performed during the past two decades on the biochemical modulation
of intravenous 5-FU by intravenous calcium leucovorin, our clinical
development of UFT proceeded to use UFT plus oral leucovorin
(Orzel).* The aim was to modulate the 5-FU generated from tegafur
biochemically via oral leucovorin. The concurrent use of UFT plus
leucovorin is now referred to as Orzel. This product reflects a
concept of dual biochemical modulation. Oral leucovorin modulates the
anabolic pathway of 5-FU via its well-described actions with
thymidylate synthase on DNA synthesis. Uracil in UFT competitively
inhibits dihydropyrimidine dehydrogenase (DPD), a key catabolic
enzyme that catabolizes approximately 80% of an administered 5-FU dose.
Phase I/II Trials
Phase I testing demonstrated that the concurrent administration of
UFT and oral leucovorin could be delivered safely, with the
dose-limiting toxic effect being diarrhea. Phase II testing in the
first-line treatment of advanced colorectal cancer patients noted
response rates, response durations, time to progression, and survival
rates similar to those reported for commonly used intravenous 5-FU
plus leucovorin schedules. However, in contrast to these intravenous
bolus schedules, UFT plus leucovorin appeared to have an improved
toxicity profilemarked reduction or absence of severe
neutropenia, febrile neutropenia, mucositis, and toxicity-related
hospitalizations. In contrast to protracted intravenous 5-FU
infusions, hand-foot syndrome was not observed, even though many
patients received UFT plus leucovorin for many months. In addition,
we noted that our patients expressed a notable preference for an oral therapy.
Phase III Trials
To confirm our phase II trials of UFT plus oral leucovorin, two large
phase III trials compared a 28-day administration schedule of UFT
plus oral leucovorin every 35 days to a commonly used 5-day
intravenous schedule of 5-FU plus leucovorin repeated monthly. One
trial, enrolling over 800 patients, randomly allocated them to
receive either UFT plus oral leucovorin or intravenous 5-FU plus
leucovorin. This trial demonstrated equivalent survival between the
two treatments. Similar response rates and response durations were
also observed. As suggested by our phase II trial, the UFT plus oral
leucovorin regimen had clinically significant safety advantages, with
a reduction in severe myelosuppression, febrile neutropenia, severe
mucositis, diarrhea, and nausea and in the use of concomitant
supportive care medications. A second trial also demonstrated similar
efficacy between the oral treatment and the intravenous treatment.
Likewise, UFT plus oral leucovorin treatment was associated with a
reduction in myelosuppression, febrile neutropenia, and severe
mucositis. Hand-foot syndrome was not evident in either trial.
The work described to date is the beginning of our exploration and
incorporation of UFT plus oral leucovorin into our treatment of
malignancies. Because of the absence of severe toxicities, UFT plus
oral leucovorin is an optimal candidate for combination chemotherapy
regimens. Its excellent acceptance by patients and well-tolerated
safety profile make it a potential therapy for patients with poor
performance status or patients who have been extensively pretreated.
Most of the work described above has concentrated on the use of UFT
plus oral leucovorin in colorectal cancer. In this disease setting,
UFT plus oral leucovorin has been investigated as the first-line
treatment of metastatic disease; combined with irinotecan (CPT-11;
Camptosar) or oxaliplatin; studied in the adjuvant setting; and
administered concurrently with pelvic irradiation to treat rectal
cancers. Discussed in this supplement is the work of additional
investigators examining UFT plus oral leucovorin alone or combined
with other agents in the treatment of gastric, breast, lung,
pancreas, and bladder carcinomas. This symposium brought
investigators from the United States, Canada, Japan, Europe, and
South America together to share their collective experiences.