In 1957, Heidelberger reported on experimental studies with a new class of tumor inhibitory compounds, the fluorinated pyrimidines. Because uracil may be preferentially used in DNA biosynthesis in tumor cells compared with normal cells, it was conjectured that a fluorine-substituted pyrimidine may be tumor specific in its inhibitory effect. Early clinical trials reported by Ansfield confirmed the importance of constant exposure to 5-fluorouracil (5-FU) to achieve a therapeutic effect, and comparison of slow-infusion 5-FU with bolus administration resulted in an increased dose with the continuous-infusion schedule. Despite this evidence, the standard 5-FU administration schedule in the 1960s and 1970s was a weekly bolus or a 5-day bolus administered at 4- or 5-week intervals.
The first reports of continuous infusional administration of 5-FU came from Wayne State University where it was observed that 5-day infusional 5-FU concomitant with radiation (and mitomycin(Drug information on mitomycin)-C) produced dramatic responses in some patients with anal cancer. This observation was followed by a prospective randomized trial reported in 1975 by Seifert et al comparing daily × 5 bolus dosing with 5-day infusion of 5-FU in advanced colon cancer. In this seminal study, response rates were doubled on the infusion schedule, though there was no effect on median survival. Methodologic problems with the study, however, included imbalances between the two treatment arms. Furthermore, at that time, the 5-day infusion required hospitalization, which greatly increased the cost and inconvenience of treatment compared with outpatient bolus delivery.
The modern era of infusional administration of 5-fluorouracil began in the early 1980s, and was aided by the availability of central venous access devices and of ambulatory infusion pumps for outpatient administration. The rationale for continuous infusion of 5-FU has always been compelling and is based on its very short half-life of 10 minutes with bolus delivery; and, as an S-phase-specific drug, 5-FU is predominantly effective in cycling cells, which represent only a small proportion of the tumor cell mass at any point in time. Schedule dependency was elegantly demonstrated in the in vitro experiments by Drewinko. In 1981, Lokich et al began to develop the concept of protracted infusional 5-FU to maximize the duration of tumor cell exposure, ultimately to achieve maximal tumor cell killing. From a series of phase I and phase II trials, several clinical effects of protracted infusional schedules became evident: (1) the optimal dose rate and maximum tolerated dose (MTD) for protracted infusion of ³ 10 weeks was 300 mg/m²/day, (2) increasing the dose rate by as little as 15% per day resulted in a substantial reduction in the duration of infusion to £ 3 weeks, (3) dose-limiting toxicity is stomatitis (diarrhea and hematologic effects are not observed), and (4) hand-foot syndrome occurs in 25% to 30% of patients. These studies also demonstrated that protracted infusion of 5-FU increased the dose intensity (as measured in mg/m²/wk) by a factor of five compared with bolus administration, with a very low incidence of toxicity.
In the early phase II studies by Lokich, response rates of 38% were observed in both previously treated and untreated patients with advanced colon cancer. Response rates in other studies ranged from 30% to 50%.[10,11]
In addition to the original Seifert trial reported in 1975, four prospective randomized trials have compared infusional 5-FU with bolus 5-FU (Table 1),[12-15] results of which have been summarized by Lokich and Anderson.[16,17] In 1989, Lokich et al reported on the first of three trials in which infusional 5-FU was evaluated by the Mid-Atlantic Oncology Program (MAOP). In this prospective randomized trial, protracted infusional 5-FU for 10 weeks was compared with a daily ´ 5 regimen repeated every 5 weeks. The response rates were statistically significantly different for the two arms (ie, 7% in the bolus arm vs 30% in the infusional arm; P = .001). Although median survival was comparable in the two arms, an analysis of proportion of patients surviving at 3 years showed a statistically significant benefit for the infusional arm.
In the two subsequent MAOP studies, protracted infusional 5-FU was used as a control arm and the experimental arm attempted to modulate infusional 5-FU. In one study, weekly cisplatin(Drug information on cisplatin) was added to infusional 5-FU. Although the addition of cisplatin did not improve response rates or survival, the results confirmed the response rate and survival pattern seen in the study comparing bolus vs infusional single-agent 5-FU. Similarly, the addition of weekly N-(phosphonacetyl)-L-aspartate (PALA) to infusional 5-FU did not increase response rate or median survival but again confirmed the consistent response rate and survival pattern for infusional 5-FU that was established in the first MAOP study.(personal communication, J. Ahlgren, MD, June, 1997)
In 1996, Hanson et al reported on an Eastern Cooperative Oncology Group (ECOG) four-arm study of 450 patients, comparing infusional 5-FU vs bolus 5-FU with or without weekly platinum. This is the only study to replicate the MAOP use of protracted infusional 5-FU at a similar dose rate. Response rates were 17% and 27%, respectively, for the bolus and infusional arms; median survivals were comparable, and platinum did not enhance therapeutic efficacy when used with either 5-FU delivery schedule.
The study by Rougier et al, involving 155 patients, has only been reported in abstract form. In this study, the infusion duration was 7 days repeated at 3-week intervals. The relative dose intensity for this dose and cycle duration is 250 mg/m²/day. Results showed that response rates doubled from 8% with the bolus schedule to 19% with infusional 5-FU (P = .02), and freedom from progression at 1 year increased from 15% to 26%, respectively (P = .04).
Finally, Weinerman et al published the National Cancer Institute of Canada data comparing bolus and infusional 5-FU in 1992. The infusion duration (14 days repeated at 4-week intervals) was intermediate between those of MAOP, ECOG, and Rougier et al, and the dose intensity (176 mg/m2/week) was the lowest used in these comparative trials. The response rate in the infusion arm was double that in the bolus arm (6% vs 12%). No difference in survival was observed, though progression-free survival was significantly longer (P = .01) in the infusion arm.
Meta-Analysis of Bolus vs Infusional 5-FU
In 1998, a meta-analysis of all randomized trials comparing infusional and bolus administration of 5-FU was published. The meta-analysis included the report by Leichman et al from the Southwest Oncology Group (SWOG) and a study by Issacson et al.[21,22] However, the SWOG study, which was actually a randomized phase II trial that involved seven different arms to assess modulation of various 5-FU administration schedules, was intended to identify activity and not to draw comparative conclusions. The study from Issacson et al is also problematic in that patients in both arms received folinic acid in addition to either bolus or infusional 5-FU. Lokich has stressed that modulation of 5-FU, when administered as an infusion, necessitates a reduction in the dose rate of infusion and increases the toxicity profile. These concerns notwithstanding, the meta-analysis was carried out with a database of 1,219 patients. Tumor response was significantly higher in the continuous-infusion arm (22% vs 14%; P = .002). Furthermore, although median survival times were close, overall survival was significantly higher for patients on infusional 5-FU (hazard ratio = 0.88; P = .04).
The concept of dose intensity, popularized by Hryniuk in breast cancer and in the use of 5-FU for colon cancer, suggests that a critical determinant of response is the dose delivered over unit time. The original reviews were based on studies in which 48-hour infusions of 5-FU were administered either weekly or at 2- or 3-week intervals. In a review by Lokich and Anderson, the more protracted infusions for 5, 7, 14 days or 10 weeks were compared (Table 2). Response rates for each of these regimens differed according to the duration of exposure; however, the dose intensity (DI) for the various regimens was substantially different. For example, for the 5-day infusion, the maximum tolerated dose was the equivalent of 35.7 mg/m²/day administered over 4 weeks. In comparison, the DI of the 4-week protracted infusion, for example, was almost ten times that at 300 mg/m²/day. In fact, the response rate was also ten times higher with the protracted infusion and higher daily dose intensity regimen (3% vs 30%). For intermediate treatment durations and dose intensities, the response rates were similarly intermediate.
It is therefore unclear whether dose intensity and duration of exposure are independent variables, although comparable response rates have been reported for the protracted 5-FU infusion when administered at 175 or 200 mg/m²/day, suggesting that infusion duration may be more important than dose intensity.
The oral fluorinated pyrimidines are compounds that may emulate the effects of parenteral continuous-infusion 5-FU. Phase III comparative trials of such agents vs bolus 5-FU/leucovorin are under way in patients with advanced colon cancer. Three of these agents are listed in Table 3, two of whichcapecitabine (Xeloda) and UFT (tegafur plus uracil)contain 5-FU as a prodrug. All of these drugs are administered on an intermittent schedule using an arbitrary 7-day rest period. These three agents and two additional fluorinated pyrimidines have been reviewed by Pazdur and by Punt. These agents emulate continuous-infusion 5-FU clinically in terms of response rates (25% to 30%) and the observation of hand-foot syndrome. However, there are some differences in the toxicity profile of the oral fluorinated pyrimidines vs parenteral infusional 5-FU. For example, diarrhea and hematologic consequences occur infrequently with low-dose protracted parenteral infusion 5-FU. For some of the oral fluorinated pyrimidines, however, diarrhea is a substantial problem and represents the most common grade 3 or 4 toxicity.
Infusional delivery of 5-FU for 24 hours per day over extended periods is superior to bolus administration of unmodulated 5-FU. Results of a meta-analysis of six phase III clinical trials carried out in the 1980s has confirmed the superior response rate and improved survival in patients receiving 5-FU by infusion. No advantage can be demonstrated for the biochemical modulation of infusional administration of 5-FU.
The new oral fluorinated pyrimidine compounds represent an important turning point in maximizing the effect of 5-FU and potentially eliminating the need for parenteral access and ambulatory infusion pumps.