Since its discovery in the late 1950s, fluorouracil(Drug information on fluorouracil) (5-FU) has been investigated in several different dosing regimens, including a daily bolus schedule for 5 consecutive days, weekly bolus schedules, and continuous infusions extending over weeks. Clinical trials have suggested the importance of constant exposure to 5-FU to obtain optimal therapeutic results. Protracted intravenous infusions appear to improve response rates and survival compared with bolus administration[3,4] and the administration of 5-FU over prolonged periods of time may also be associated with reduced toxicity.[3,5] The toxicity profile of 5-FU is schedule dependent. While stomatitis and hand-foot syndrome (palmar-plantar erythrodysesthesia) are associated with continuous or protracted infusions, neutropenia and diarrhea are the dose-limiting toxicities of bolus schedules.[3,6]
One approach to improving the activity of 5-FU has been the addition of biochemical modulators. Several modulators have been studied, including leucovorin, N-(phosphonacetyl)-L-aspartate (PALA), methotrexate(Drug information on methotrexate), trimetrexate(Drug information on trimetrexate), and interferon alfa.
Leucovorin is the most extensively used 5-FU biochemical modulator. In a meta-analysis of nine randomized clinical trials of advanced colorectal cancer comparing 5-FU alone with 5-FU plus IV leucovorin, patients receiving 5-FU/leucovorin showed a significant improvement in response rate in comparison with patients receiving 5-FU alone. However, improvement in response rates failed to convey a significant survival advantage.
The dose and schedule of leucovorin required for the optimal modulation of 5-FU has not been clearly defined. Leucovorin doses ranging from 20 to 500 mg/m2/d have been administered on daily x 5 days, bimonthly, or weekly schedules. A low-dose leucovorin regimen (leucovorin at 20 mg/m2/d plus 5-FU at 425 mg/m2/d for 5 consecutive days administered every 4 to 5 weeks) is commonly used in the United States, both for the treatment of metastatic colorectal cancer and as adjuvant therapy. This schedule often serves as a standard regimen in phase III advanced colorectal cancer trials evaluating new agents. Another commonly used regimen is a weekly regimen (leucovorin at 500 mg/m2 plus 5-FU at 500 mg/m2 administered weekly for 6 consecutive weeks followed by a 2-week rest).
These two regimens have similar response rates and survival. The median survival of advanced colorectal cancer patients treated with these regimens is approximately 1 year. Dose-limiting (grade 3/4) toxicities of the low-dose regimen are primarily oral mucositis (24% of patients) and neutropenia (29% of patients), whereas diarrhea is the predominant toxicity of the weekly regimen (32% of patients). These regimens of 5-FU plus leucovorin have been associated with toxicity-related hospitalizations in 20% to 30% of treated patients.
Although the modulation of 5-FU by leucovorin has been suggested as a standard of care for patients with metastatic colorectal cancer, a Southwest Oncology Group (SWOG) trial suggested that a protracted infusion of 5-FU has a favorable toxicity profile and trend toward improved survival compared with six other 5-FU regimens. This trial randomly allocated 500 patients to receive one of the following treatments: 5-FU IV bolus, 5-FU plus low-dose oral leucovorin, 5-FU plus high-dose leucovorin, 5-FU continuous infusion, 5-FU 24-hour infusion, and 5-FU 24-hour infusion plus PALA. Response rates ranged between 15% and 29% with a median survival for the entire group of 14 months.
An alternative schedule of 5-FU plus leucovorin uses a bimonthly high-dose leucovorin and 5-FU regimen. The schedule, investigated by de Gramont et al, has been extensively examined in France. This bimonthly schedule was compared to the low-dose leucovorin schedule (daily x 5). The investigators observed a more favorable toxicity profile and higher response rate for the bimonthly schedule. However, no statistically significant improvement in overall survival was noted with the bimonthly schedule.
The combination of interferon alfa plus 5-FU appeared promising in phase II studies of patients with metastatic colorectal cancer.[12-14] Unfortunately, randomized phase III trials that compared the combination of 5-FU plus interferon either with 5-FU alone or 5-FU plus leucovorin concluded that interferon afforded no benefit with regard to response rates and overall survival. Toxicity in the interferon arm increased significantly.
Trimetrexate, another dihydrofolate reductase inhibitor, potentiates the cytotoxicity of 5-FU. Phase II studies demonstrated objective responses with trimetrexate in combination with high-dose leucovorin and 5-FU in patients previously treated with 5-FU chemotherapy. However, grade 3 or 4 diarrhea and hypersensitivity occurred.
Several new agents are under development for the treatment of colorectal cancer. Some of these, including oral fluoropyrimidines, oxaliplatin(Drug information on oxaliplatin), and irinotecan(Drug information on irinotecan) (Camptosar, CPT-11), are reviewed herein.
A protracted IV infusion of 5-FU may be an optimal schedule, resulting in continuous exposure of tumor cells to active 5-FU concentrations. This delivery system requires indwelling catheters, which can lead to line infection, line slippage, or thrombosis. Oral dosing of fluoropyrimidines would circumvent this problem. The bioavailability of oral 5-FU has been demonstrated to be erratic, precluding reliable dosing by this administration route. The erratic absorption of 5-FU may be attributed to varying levels of dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract. DPD is the primary catabolic enzyme of 5-FU with an estimated 85% of an administered 5-FU dose being catabolized by this enzyme. This problem of erratic 5-FU absorption from the gastrointestinal tract was overcome by the development of 5-FU prodrugs that are well absorbed enterally and then enzymatically converted to 5-FU. A second method to circumvent inconsistent oral absorption of 5-FU is to inactivate DPD.