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 adjuvant setting.
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.