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

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(Drug information on irinotecan) (CPT-11; Camptosar) or oxaliplatin(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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.