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The University of Texas M. D. Anderson Cancer Center Orzel/UFT Investigators’s Workshop and Consensus Conference

The University of Texas M. D. Anderson Cancer Center Orzel/UFT Investigators’s Workshop and Consensus Conference


Supported by an unrestricted educational grant from Bristol-Myers Squibb
Oncology and Taiho Pharmaceutical Co., Ltd.


Beyond 5-Fluorouracil

Richard Pazdur, MD
Professor of Medicine, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas

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. This symposium
brought investigators from the United States, Canada, Japan, Europe,
and South America together to share their collective experiences.
Most of the work 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.

Clinical Implications of Dihydropyrimidine Dehydrogenase Inhibition

Robert B. Diasio, MD
Chairman, Department of Pharmacology/Toxicology, and Director,
Division of Clinical Pharmacology, and Associate Director, University
of Alabama Cancer Center, University of Alabama at Birmingham ,
Birmingham, Alabama

Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting
enzyme in the catabolism of 5-fluorouracil (5-FU). DPD has an
important role in regulating the availability of 5-FU for anabolism.
It is now clear that DPD also accounts for much of the variability
observed with the therapeutic use of 5-FU, including variable drug
levels during 24-hour infusion, erratic pharmacokinetics, variable
bioavailability, inconsistent toxicity, and variability in drug
response (resistance). The use of DPD inhibitors has been explored as
a means to improve 5-FU pharmacology. This article describes how
drugs that modulate DPD activity have been used to develop a new
class of orally administered fluoropyrimidines, now referred to as
DPD-inhibiting fluoropyrimidine (DIF) drugs. The biochemical basis
for using four DIF drugs—uracil and tegafur (UFT),
ethynyluracil, S-1, and BOF-A2—currently in clinical evaluation
in the United States, is hereby reviewed. Early clinical data suggest
that these drugs may achieve antitumor efficacy equivalent to that of
conventional intravenously administered 5-FU therapy, with the
additional advantages of reduced toxicity, less expense, and improved
quality of life.

Clinical Implications of Dihydropyrimidine Dehydrogenase Inhibition

Robert B. Diasio, MD
Chairman, Department of Pharmacology/Toxicology, and Director,
Division of Clinical Pharmacology, and Associate Director, University
of Alabama Cancer Center, University of Alabama at Birmingham ,
Birmingham, Alabama

Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting
enzyme in the catabolism of 5-fluorouracil (5-FU). DPD has an
important role in regulating the availability of 5-FU for anabolism.
It is now clear that DPD also accounts for much of the variability
observed with the therapeutic use of 5-FU, including variable drug
levels during 24-hour infusion, erratic pharmacokinetics, variable
bioavailability, inconsistent toxicity, and variability in drug
response (resistance). The use of DPD inhibitors has been explored as
a means to improve 5-FU pharmacology. This article describes how
drugs that modulate DPD activity have been used to develop a new
class of orally administered fluoropyrimidines, now referred to as
DPD-inhibiting fluoropyrimidine (DIF) drugs. The biochemical basis
for using four DIF drugs—uracil and tegafur (UFT),
ethynyluracil, S-1, and BOF-A2—currently in clinical evaluation
in the United States, is hereby reviewed. Early clinical data suggest
that these drugs may achieve antitumor efficacy equivalent to that of
conventional intravenously administered 5-FU therapy, with the
additional advantages of reduced toxicity, less expense, and improved
quality of life.

Clinical Implications of 5-FU Modulation

Youcef M. Rustum, PhD
Senior Vice President for Scientific Affairs, and Professor of
Molecular Pharmacology, Roswell Park Cancer Institute Buffalo, New York

In recent years, due to the advent of sensitive instrumentation and
methodologies, it has been possible to identify parameters that
predict the quality of response of individual patients to treatments
for specific selected diseases, eg, colon carcinoma and breast
carcinoma. Ongoing studies are attempting to identify sensitive
patients in order to select treatment regimens suitable for the
individual patient. The critical question that remains is whether the
basis for drug resistance is due in part to insufficient delivery of
drugs to target tumor cells or to the resistance of target tumor
cells by various mechanisms, including, in the case of 5-fluorouracil
(5-FU), drug transport, metabolism, expression of the target enzyme
thymidylate synthase (dTMPS), depletion of folate cofactors, and/or
level of competing substrate deoxyuridine monophosphate. Also in
recent years, attempts have been made to delineate mechanisms of
resistance to the fluoropyrimidines. On the basis of such studies, it
may be possible to develop approaches aimed at the selective
modulation of the therapeutic efficacy of these agents in tumor
tissues with varying degrees of sensitivity to fluoropyrimidines, eg,
patients with advanced colorectal cancer. One such approach is the
use of calcium folinate to modulate the therapeutic efficacy of 5-FU.

Schedule Dependency of 5-Fluorouracil

Cynthia Gail Leichman, MD
Department of Medicine, Roswell Park Cancer Institute, Buffalo,
New York

5-Fluorouracil (5-FU) is cell-cycle specific for its cytotoxicity and
has a pharmacokinetic profile characterized by a short, single-dose
half-life of 10 to 20 minutes in plasma. Efforts to maximize its
clinical efficacy have been directed at overcoming this short
half-life. Strategies have included prolonging intracellular exposure
by biochemical modulation or administration by infusional schedules,
and more recently by chronic oral dosing. A number of clinical trials
comparing routes of administration and biochemical modulation of 5-FU
are presented in this article. Issues of dose intensity, differing
toxicity profiles, and pharmacoeconomics are reviewed.

Toxicity of 5-Fluorouracil

John S. Macdonald, MD
Professor of Medicine, and Chief, Gastrointestinal Oncology
Service, St. Vincents Comprehensive Cancer Center, New York, New York

Fluorouracil (5-FU) is a relatively unique drug in oncology because
administration in different doses and schedules results in
dramatically different patterns of qualitative toxicity. In the 41
years 5-FU has been available to the clinical oncologist, a wide
variety of doses and schedules of this agent have been used.
Infusional schedules are associated with less myelosuppression but
may have more gastrointestinal and skin toxicity. Bolus schedules
cause myelotoxicity, and bolus schedules including calcium folinate
are associated with diarrhea, mucositis, and, in some schedules,
myelosuppression. The availability of various doses and schedules of
5-FU for administration allows clinicians to choose a 5-FU regimen
with the most acceptable pattern of toxicity for individual cases.
Also, the study of 5-FU in various groups of patients has
demonstrated that relatively increased drug toxicity may be expected
in patients above the age of 70 years and in female patients.

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