The use of concomitant chemoradiotherapy has a strong theoretical and practical rationale, and combined-modality treatment has proven effective for a variety of human solid malignancies. Multiple prospective randomized trials have demonstrated improved local control and survival for patients with locally advanced, nonmetastatic gastrointestinal malignancies treated with 5-fluorouracil (5-FU)based chemoradiotherapy, compared to 5-FU or radiation therapy alone. While the mechanism(s) for the interaction has not been precisely defined, chemotherapy may increase the activity of radiation therapy through direct and selective eradication of radioresistant cells or through a cellular interaction with radiation therapy, leading to inhibition of structural repair and resulting in decreased radioresistance.
5-FU appears to be a more effective radiosensitizer when given by continuous intravenous infusion; however, that mode of administration is cumbersome. Uracil and tegafur(Drug information on tegafur) (in a molar ratio of 4:1 [UFT]), an oral 5-FU prodrug, behaves pharmacologically like continuous intravenous infusion 5-FU and is a logical choice for combination with radiation therapy. This article reviews the structure and activity of both 5-FU and UFT, the use of fluoropyrimidines with radiation therapy, and ongoing trials of UFT as a component in combined-modality therapy.
5-FU has been a mainstay in the solid tumor chemotherapy armamentarium for more than 40 years. During this time, numerous attempts to bolster its effectiveness have been made, both by changing the route of administration and through modulation by codelivery with other agents. Despite these attempts, reported response rates remain low, and administration remains burdensome, requiring intravenous access and multiple patient clinic visits per cycle.
5-FU is a rationally designed compound synthesized by Heidelberger several decades ago. It belongs to the antimetabolite class of antineoplastics and is a pyrimidine antagonist that resembles uracil, substituting fluorine for hydrogen at position 5 (Figure 1). At least three major mechanisms of action have been postulated for 5-FU, all involving activation by metabolism to various nucleotides.[2,3] 5-FU is converted to 5-fluoro-2¢deoxyuridine (FUdR) by thymidine phosphorylase. FUdR is then further phosphorylated by thymidine kinase to 5-fluoro-2¢deoxyuridine monophosphate (FdUMP). FdUMP forms a stable covalent compound with thymidylate synthase, leading to the inhibition of that enzyme with subsequently decreased de novo synthesis of thymidine monophosphate (dTMP). This ultimately results in substandard DNA synthesis and repair.
A controversial proposed mechanism of action involves 5-FU incorporation through fluorodeoxyuridine triphosphate (FdUTP) into DNA. DNA synthesized in the presence of 5-FU has a markedly smaller strand size and is more prone to strand breaks. This fragility may result from the actual excision of 5-FU from the DNA or may be related to inefficient repair of normally occurring trauma. However, the extent to which this incorporation is related to cytotoxicity, particularly the magnitude of the effect from thymidylate synthase inhibition, continues to be debated.
Finally, 5-FU is somewhat unique in that it is extensively incorporated through fluorouridine triphosphate (FUTP) into all classes of RNA, where it leads to misprocessing and/or misfunction. This clearly correlates with cytotoxicity in various solid tumor cell lines.
5-FU is not convenient to administer. Oral bioavailability varies from 28% to 100%. Conventional IV bolus dosing leads to short periods (less than a few hours) during which plasma concentrations are above the putative cytotoxic level. Thymidylate synthase inhibition in particular is S-phase dependent, so the 6- to 20-minute half-life following bolus administration does not seem to overlap cell division for most of a bulky solid tumor and should not be the major mechanism of action for bolus 5-FU.
Continuous IV infusion is a logical choice to overcome the short half-life of the drug. Continuous intravenous infusion clearly has a different spectrum of toxicity than bolus administration, as well as a different maximum tolerated dose and achievable dose intensity. Cells resistant to bolus 5-FU occasionally remain sensitive to continuous intravenous infusion, suggesting there may actually be a different mechanism of action for that delivery system or that it leads to a shift in the relative importance of each of the three potential mechanisms for 5-FU discussed above. An alternate explanation is that patients receiving continuous intravenous infusion 5-FU achieve a 3- to 4-fold increase in cumulative dose vs bolus.
Continuous intravenous infusion 5-FU, administered during radiation therapy in the adjuvant treatment of rectal cancer, clearly leads to improved survival over bolus therapy. However, even in the absence of radiation therapy, continuous intravenous infusion 5-FU remains superior for the treatment of metastatic large bowel tumors. A recent meta-analysis comparing the administration of 5-FU by continuous intravenous infusion vs bolus found the response rate was significantly higher for continuous intravenous infusion (22% vs 14%), which translated to a small overall survival benefit (hazards ratio 0.88). However, continuous intravenous infusion 5-FU is even more inconvenient to administer, requiring a secure form of venous access, as well as the use of an ambulatory infusion pump.
Heidelberger and colleagues discovered that growth inhibitory doses of radiation therapy in rodent tumors were made cytotoxic by the addition of 5-FU. Conversely, ineffective 5-FU regimens became active with the addition of a single fraction of radiation therapy. These synergistic effects have subsequently been confirmed by many other investigators, using both in vitro and in vivo models.[9-15] Randomized trials have demonstrated that the combination of 5-FU and radiation therapy significantly improves local control and survival for patients with a wide variety of solid tumors, compared to radiation therapy or chemotherapy alone.[16-18]
The mechanism of 5-FU radiosensitization is poorly understood, and the best timing for administration of the two modalities is not precisely defined. There are several possible explanations for radiation sensitization by 5-FU, and more than one type of interaction is possible. FdUMP-mediated inhibition of thymidylate synthase with resulting thymidine triphosphate (dTTP) pool depletion, enhanced DNA damage, interference with DNA repair, and cell-cycle effects all may contribute to radiosensitization. Indeed, some in vitro models have shown that 5-FU increases the steepness of the radiation survival curve, while others have demonstrated that 5-FU reduces the shoulder of the curve (which represents the capacity for DNA repair) without affecting the slope. The underlying mechanisms for the 5-FU/radiation-therapy interaction may be influenced by drug dose, timing of administration, and duration of 5-FU exposure.
Byfield et al reported that combined treatment with 5-FU and radiation therapy leads to time-dependent and dose-dependent enhancement of cell killing in HeLa cervical cancer and HT-29 colon cancer cells. Enhanced radiosensitization was dependent on cell exposure to 5-FU for periods longer than the cell-doubling time. Optimal effects were observed when cells were exposed to 5-FU for 48 hours following radiation therapy, with little or no synergy observed when the drug was given either before or for 3 to 24 hours after radiation therapy. The authors concluded that radiation therapy enhancement was not related to either an infliction of additional acute damage by drug in the immediate postradiation-therapy period or to an inhibitory effect on repair of sublethal radiation- therapyinduced damage.
Other investigators have suggested that alternate timing and modes of 5-FU administration can also lead to radiosensitization. Smalley and associates reported that 5-FU modulation of radiosensitivity in DU-145 human prostate cancer cells was evident with radiation therapy delivered during a 1-hour pulse of 5-FU, as well as with radiation therapy given either immediately before 5-FU or 17 hours after 5-FU. Using a solid tumor model, Loony and associates observed that maximal inhibition of tumor growth occurred when 5-FU was administered 4 days after radiation therapy, with this combination being 2.5-fold more effective than that expected if effects were merely additive. Beaupain and colleagues showed the administration of 5-FU preceding radiation therapy to be the most effective schedule in growth inhibition of human pulmonary cancer nodules maintained in continuous organotypic culture. Weinberg and associates found no schedule dependency for 5-FU/radiation-therapy enhancement in an in vitro squamous cell carcinoma model, though there was clear dose dependency. These studies clearly demonstrate that there is substantial heterogeneity in cell radiosensitivity modulation by 5-FU.
FUdR is an interesting drug with which to study fluoropyrimidine-mediated radiosensitization. As a radiosensitizer, FUdR is effective in concentrations at which it would only achieve thymidylate synthase inhibition and would not demonstrate the more complex interactions other fluoropyrimidines show with DNA and RNA. Clearly, FUdR has been shown to be a potent radiosensitizer of HT-29 and HuTu80 human colon cancer cells.[23,24] Although sensitization has been produced under a wide range of exposure conditions, FUdR is substantially more effective when it precedes radiation therapy for 2 hours compared with when it follows radiation therapy. Sensitization correlates with thymidylate synthase inhibition and depletion of dTTP pools, and is blocked by coincubation with thymidine. However, 8- or 24-hour pre-exposures to low concentrations of FUdR can also enhance radiation-therapyinduced DNA damage, apparently by inhibiting repair of DNA double-strand breaks.
Both 5-FU and FUdR treatment arrest S-phase cells and block cells in early S-phase (G1/S interphase) 16 to 32 hours following fluoropyrimidine exposure. Early S-phase is thought to represent a relatively radiosensitive portion of the cell cycle, but some investigators have found that the fraction of cells in early S-phase is a weak predictor of radiation therapy enhancement. Lawrence and colleagues demonstrated that HT-29 cells with blocked S-phase progression are not radiosensitized by FUdR. Using a population of synchronized HT-29 cells, McGinn and associates examined radiation therapy survival data with FUdR and concluded early S-phase delay is not the primary means of radiosensitization, although there is an association between early S-phase enrichment and radiosensitization. Overall, experts suggest radiosensitization is partially but not completely due to redistribution of cells through the cell cycle, or at least to an alteration of the G1/S check point.